rs199903114

Positions:

• chr2-151684842-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001164507.2(NEB):​c.2771A>C​(p.Tyr924Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,426 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).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28590214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.2771A>C	p.Tyr924Ser	missense_variant	28/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.2771A>C	p.Tyr924Ser	missense_variant	28/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.2771A>C	p.Tyr924Ser	missense_variant	28/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.2771A>C	p.Tyr924Ser	missense_variant	28/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.2771A>C	p.Tyr924Ser	missense_variant	28/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000262 AC: 65 AN: 248142 Hom.: 0 AF XY: 0.000334 AC XY: 45 AN XY: 134558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461066 Hom.: 0 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 726758

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000351 Hom.: 1

Bravo AF: 0.000174

ExAC AF: 0.000298 AC: 36

EpiCase AF: 0.000873

EpiControl AF: 0.000774

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NEB: PM2, BP1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	Identified in a patient with adult-onset myopathy along with NEB variant c.21790G>C. The phase of these two variants (cis/trans) is unknown (Poster presentation; Morales et al., 2017); Also reported in one patient in association with endometriosis; however, rurther research is needed to explore a possible link between variants in the NEB gene and this phenotype (PMID: 37626618); 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: 37626618) -

Nemaline myopathy 2 Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.2771A>C (p.Y924S) alteration is located in exon 28 (coding exon 26) of the NEB gene. This alteration results from a A to C substitution at nucleotide position 2771, causing the tyrosine (Y) at amino acid position 924 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;.;T;.;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;.
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;T;.;T;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.97	.;.;.;.;D;.;.
Vest4		0.75
MVP		0.57
MPC		0.39
ClinPred		0.31	T
GERP RS		5.3
Varity_R		0.68
gMVP		0.43

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: rs199903114; hg19: chr2-152541356; COSMIC: COSV51473361; COSMIC: COSV51473361;