NM_001164507.2:c.3874A>G

Variant names:

• chr2-151675292-T-C
• rs1553521537
• NM_001164507.2:c.3874A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001164507.2(NEB):​c.3874A>G​(p.Ser1292Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,421,136 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 5.44
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-151675292-T-C is Pathogenic according to our data. Variant chr2-151675292-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551937.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3874A>G	p.Ser1292Gly	missense_variant	Exon 35 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3874A>G	p.Ser1292Gly	missense_variant	Exon 35 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3874A>G	p.Ser1292Gly	missense_variant	Exon 35 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3874A>G	p.Ser1292Gly	missense_variant	Exon 35 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3874A>G	p.Ser1292Gly	missense_variant	Exon 35 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421136 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 704886

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.00 AC: 0 AN: 40876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38986

South Asian (SAS) AF: 0.00 AC: 0 AN: 81752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1084458

Other (OTH) AF: 0.00 AC: 0 AN: 59020

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:1 Uncertain:1

May 19, 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.

Jun 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nemaline myopathy 2 (PMID: 25473036). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551937). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1292 of the NEB protein (p.Ser1292Gly).

Nemaline myopathy Pathogenic:1

Mar 20, 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.Ser1292Gly variant in NEB has been reported, in the compound heterozygous state, in 1 individual with nemaline myopathy, segregated with disease in 2 affected relatives (PMID: 25473036), and has been identified in 0.0002% (2/1152484) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1553521537). 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. This variant has also been reported in ClinVar (Variation ID: 551937) and has been interpreted as pathogenic by Invitae and a variant of uncertain significance by Counsyl and Baylor Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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, PP1, PM2_supporting (Richards 2015).

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

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arthrogryposis multiplex congenita 6 Uncertain:1

May 18, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;T;.;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
PhyloP100		5.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;N;.;N;N;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.012	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Vest4		0.71
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.53
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1553521537; hg19: chr2-152531806;