rs549794342

Variant names:

• chr2-151501423-G-A
• rs549794342
• NM_001164507.2:c.23989C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151501423-G-A
• chr2-151501423-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001164507.2(NEB):​c.23989C>T​(p.Arg7997*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,548,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: NEB NM_001164507.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:2
• Conservation: PhyloP100: 0.865
• Publications: 3 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-151501423-G-A is Pathogenic according to our data. Variant chr2-151501423-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373977.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000272 AC: 43 AN: 157874 AF XY: 0.000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.000310 AC: 433 AN: 1396230 Hom.: 0 Cov.: 29 AF XY: 0.000335 AC XY: 231 AN XY: 688560

African (AFR) AF: 0.0000951 AC: 3 AN: 31546

American (AMR) AF: 0.0000841 AC: 3 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 25088

East Asian (EAS) AF: 0.00 AC: 0 AN: 35796

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78496

European-Finnish (FIN) AF: 0.000793 AC: 39 AN: 49174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000339 AC: 365 AN: 1076946

Other (OTH) AF: 0.000329 AC: 19 AN: 57838

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74394

African (AFR) AF: 0.0000723 AC: 3 AN: 41514

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.000218 AC: 19

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:20 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:8

Aug 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a pregnancy loss with an unspecified fetal anomaly (PMID: 33100332); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 32721234, 31589614, 33100332, 39802796, 38167091) -

Nov 09, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PVS1 -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB: PVS1, PM2:Supporting -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Pathogenic:6 Uncertain:1

Oct 04, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 168 of 182 is predicted to result in loss of normal protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (61/183470) and thus is presumed to be rare. This variant has been classified as likely pathogenic by several clinical diagnostic labs in the ClinVar database (Variation ID: 373977). Based on the available evidence, the c.23989C>T (p.Arg7997Ter) variant is classified as likely pathogenic. -

Oct 01, 2019

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 20, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nemaline myopathy 2, autosomal recessive (MIM#256030). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). In silico splice site analysis of this variant may also result in activation of a cryptic 5' splice site resulting in a frameshift (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with nemaline myopathy 2, autosomal recessive (MIM#256030) (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg8032*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs549794342, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 373977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:2

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nemaline myopathy Pathogenic:1 Uncertain:1

Feb 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.24094C>T (p.Arg8032X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00027 in 157874 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00027 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.24094C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 26, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg7997Ter (p.Arg8032Ter) variant in NEB has not been previously reported in the literature in individuals with nemaline myopathy, and has been identified in 0.07% (41/59758) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549794342). This variant has been seen in the general population, in a heterozygous state, at a greater rate than expected for the disorder. The p.Arg7997Ter variant has been reported in several publications, but never in cases with an established diagnosis with nemaline myopathy. This variant has been detected in carriers and in cases with non-specific phenotype or pregnancy loss due to fetal anomaly (Personal communication, PMID: 33100332, 32721234, 31980526, 31589614, 38167091). This variant has also been reported in ClinVar (Variation ID: 373977) and has been interpreted as pathogenic/likely pathogenic by multiple submitters and as a variant of uncertain significance by Counsyl. This nonsense variant leads to a premature termination codon at position 7997, which is predicted to lead to a truncated or absent protein. Expression data indicates that this exon might not be biologically relevant for this disease, and therefore this variant may not result in loss of function of NEB. Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, the clinical significance of the p.Arg7997Ter variant is uncertain. ACMG/AMP Criteria applied: PVS1, BS1 (Richards 2015). -

NEB-related disorder Pathogenic:1

Mar 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEB c.24094C>T variant is predicted to result in premature protein termination (p.Arg8032*). This variant was reported in an individual as part of a large genome-wide sequencing study and classified as likely pathogenic (Hou et al. 2020. PubMed ID: 31980526). This variant has also been reported with a second NEB variant in a pregnancy loss with fetal anomalies (Zhao et al. 2021. PubMed ID: 33100332). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NEB are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by several independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/373977/). This variant is interpreted as likely pathogenic. -

Muscular dystrophy;C0030196:Limb pain;C1836156:Progressive proximal muscle weakness Pathogenic:1

Sep 15, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	46
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		0.86
Vest4		0.76
ClinPred		0.35	T
GERP RS		-2.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: -32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs549794342; hg19: chr2-152357937;