rs541803470

Variant names:

• chr2-151671192-C-A
• rs541803470
• NM_001164507.2:c.4337G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151671192-C-A
• chr2-151671192-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001164507.2(NEB):​c.4337G>T​(p.Gly1446Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,608 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1446D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.84
• Publications: 2 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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 2-151671192-C-A is Pathogenic according to our data. Variant chr2-151671192-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.4337G>T	p.Gly1446Val	missense_variant	Exon 38 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.4337G>T	p.Gly1446Val	missense_variant	Exon 38 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.4337G>T	p.Gly1446Val	missense_variant	Exon 38 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.4337G>T	p.Gly1446Val	missense_variant	Exon 38 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.4337G>T	p.Gly1446Val	missense_variant	Exon 38 of 150	5		ENSP00000386259.1
NEB	ENST00000484968.1	n.189G>T		non_coding_transcript_exon_variant	Exon 1 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249100 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461608 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111792

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy Pathogenic:2

Aug 16, 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.4337G>T (p.Gly1446Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249100 control chromosomes (gnomAD). c.4337G>T has been reported in the literature as a compound heterozygous genotype with other deleterious variants in at least three unique individuals affected with Nemaline Myopathy 2 (e.g., Lehtokari_2014, Hindocha_2017). At least one of these individuals was comprehensively phenotyped with features of congenital nemaline myopathy co-presenting with systemic lupus erythematosus (Hindocha_2017). 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. The following publications have been ascertained in the context of this evaluation (PMID: 28977494, 25205138). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mar 18, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly1446Val variant in NEB has been reported in 3 individuals with nemaline myopathy (PMID: 25205138, 28977494), and has been identified in 0.002% (18/1179816) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs541803470). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 3 affected individuals, 2 were a compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly1446Val variant is pathogenic (Variation ID: 2677073, 918157; PMID: 28977494, 25205138). This variant has also been reported in ClinVar (Variation ID:551527) and has been interpreted as likely pathogenic by Women's Health and Genetics/Laboratory Corporation of America, and a variant of uncertain significance by Counsyl. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for nemaline myopathy based on the presence of nemaline rods on a muscle biopsy consistent with disease (PMID: 28977494). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PP3_moderate, PM3, PP4, PM2_supporting (Richards 2015). -

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

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Uncertain:1

Apr 14, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;T;.;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.4	M;M;.;M;M;M;M
PhyloP100		7.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.4	D;D;.;D;D;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.95
MutPred		0.80		Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);Gain of ubiquitination at K1445 (P = 0.0555);
MVP		0.61
MPC		0.38
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.71
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs541803470; hg19: chr2-152527706;