rs769345284

Variant names:

• chr2-151537898-G-A
• rs769345284
• NM_001164507.2:c.21076C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151537898-G-A
• chr2-151537898-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164508.2(NEB):​c.21076C>T​(p.Arg7026*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000171 in 1,459,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NEB NM_001164508.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.90

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]

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-151537898-G-A is Pathogenic according to our data. Variant chr2-151537898-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151537898-G-A is described in Lovd as [Pathogenic]. Variant chr2-151537898-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-151537898-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.21076C>T	p.Arg7026*	stop_gained	Exon 140 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.21076C>T	p.Arg7026*	stop_gained	Exon 140 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21076C>T	p.Arg7026*	stop_gained	Exon 140 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.21076C>T	p.Arg7026*	stop_gained	Exon 140 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000323 AC: 8 AN: 247458 AF XY: 0.0000447

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1459460 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 725866

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33388

Gnomad4 AMR exome AF: 0.0000225 AC: 1 AN: 44430

Gnomad4 ASJ exome AF: 0.0000384 AC: 1 AN: 26074

Gnomad4 EAS exome AF: 0.0000505 AC: 2 AN: 39622

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85690

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53356

Gnomad4 NFE exome AF: 0.0000162 AC: 18 AN: 1110866

Gnomad4 Remaining exome AF: 0.0000332 AC: 2 AN: 60280

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000145 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:4

Nov 27, 2024

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.Arg7026*) 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 (rs769345284, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 25205138, 26841830). ClinVar contains an entry for this variant (Variation ID: 190457). For these reasons, this variant has been classified as Pathogenic. -

Jan 06, 2017

Counsyl

Significance: Pathogenic

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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nemaline myopathy Pathogenic:1

May 14, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.21076C>T (p.Arg7026X) 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 (eg. c.24407_24410dupTGTT, p.Leu8137fsX18; c.24559C>T, p.Arg8187X). The variant allele was found at a frequency of 3.3e-05 in 244554 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (3.3e-05 vs 0.0035), allowing no conclusion about variant significance. The variant, c.21076C>T, has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Lehtokari_2014, Oliveira_2016, Park_2018), as well as in a family with recurrent fetal loss in the homozygous state (Shamseldin_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Non-immune hydrops fetalis Pathogenic:1

Dec 15, 2013

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:1

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: 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	0.52	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	49
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.99
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769345284; hg19: chr2-152394412; COSMIC: COSV50829439;