rs193224180

Variant names:

• chr2-151503408-G-A
• rs193224180
• NM_001164507.2:c.23776C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164507.2(NEB):​c.23776C>T​(p.Pro7926Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,612,560 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: 3.94
• Publications: 5 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021578938).
• BP6: Variant 2-151503408-G-A is Benign according to our data. Variant chr2-151503408-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194312.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (205/152262) while in subpopulation NFE AF = 0.00256 (174/68010). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.23881C>T	p.Pro7961Ser	missense	Exon 167 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23776C>T	p.Pro7926Ser	missense	Exon 166 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.18673C>T	p.Pro6225Ser	missense	Exon 139 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00110 AC: 274 AN: 248950 AF XY: 0.00107

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00186 AC: 2719 AN: 1460298 Hom.: 6 Cov.: 29 AF XY: 0.00173 AC XY: 1260 AN XY: 726472

African (AFR) AF: 0.000389 AC: 13 AN: 33428

American (AMR) AF: 0.00112 AC: 50 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00228 AC: 2532 AN: 1110780

Other (OTH) AF: 0.00194 AC: 117 AN: 60328

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74446

African (AFR) AF: 0.000313 AC: 13 AN: 41568

American (AMR) AF: 0.000654 AC: 10 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68010

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000546 AC: 2

ESP6500EA AF: 0.00293 AC: 24

ExAC AF: 0.000952 AC: 115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEB p.Pro7926Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs193224180), ClinVar (classified as likely benign by EGL Genetics and as a VUS by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine and Invitae for nemaline myopathy 2) and LOVD 3.0. The variant was identified in control databases in 316 of 280356 chromosomes at a frequency of 0.001127 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 260 of 128302 chromosomes (freq: 0.002026), Latino in 38 of 35298 chromosomes (freq: 0.001077), Other in 6 of 7122 chromosomes (freq: 0.000843), African in 8 of 24192 chromosomes (freq: 0.000331), European (Finnish) in 3 of 25010 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10348 chromosomes (freq: 0.000097); it was not observed in the East Asian and South Asian populations. The p.Pro7926 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Dec 06, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 08, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a child with congenital cataracts, ptosis, hypotonia, delay in motor skills, dysphagia, and respiratory failure, who has variants in multiple other genes (PMID: 32420686); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32420686)

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB: BS1

May 15, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nemaline myopathy 2 Uncertain:2 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Mar 23, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro7961Ser va riant in NEB has not been previously reported in individuals with myopathy, but has been identified in 0.15% (97/66646) of European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193224180). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Pro7961Ser variant is uncertain, these data suggest that it is more likely to be benign.

Inborn genetic diseases Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.18673C>T (p.P6225S) alteration is located in exon 139 (coding exon 137) of the NEB gene. This alteration results from a C to T substitution at nucleotide position 18673, causing the proline (P) at amino acid position 6225 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

NEB-related disorder Benign:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.13
Sift	Benign	0.32	T
Sift4G	Uncertain	0.016	D
Polyphen		0.20	B
Vest4		0.63
MVP		0.38
MPC		0.33
ClinPred		0.051	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.31
Mutation Taster		=245/55	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs193224180; hg19: chr2-152359922;