rs201886728

Positions:

• chr2-151562640-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164508.2(NEB):​c.18862G>A​(p.Val6288Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,581,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 7.91

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071285695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18862G>A	p.Val6288Ile	missense_variant	120/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18862G>A	p.Val6288Ile	missense_variant	120/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18862G>A	p.Val6288Ile	missense_variant	120/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18862G>A	p.Val6288Ile	missense_variant	120/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000373 AC: 91 AN: 244090 Hom.: 0 AF XY: 0.000340 AC XY: 45 AN XY: 132246

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.000305

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000791 AC: 1131 AN: 1429132 Hom.: 0 Cov.: 30 AF XY: 0.000759 AC XY: 535 AN XY: 705228

Gnomad4 AFR exome AF: 0.000213

Gnomad4 AMR exome AF: 0.000501

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000253

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.000942

Gnomad4 OTH exome AF: 0.000918

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74380

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.000480 AC: 4

ExAC AF: 0.000331 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 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	Oct 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	Identified in an individual with endometriosis, however additional clinical information was not provided; this individual also harbored variants in several other genes that may have contributed to the phenotype (PMID: 37626618); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37626618) -

Nemaline myopathy 2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

The c.13759G>A (p.V4587I) alteration is located in exon 93 (coding exon 91) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 13759, causing the valine (V) at amino acid position 4587 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	.;.;T;.;T;T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0050
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;.;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.071	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.;.;.;N;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.65	N;N;.;N;N;N;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.013	D;T;.;T;D;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		0.27	.;.;.;.;B;.;.;.
Vest4		0.28
MVP		0.46
MPC		0.13
ClinPred		0.070	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs201886728; hg19: chr2-152419154; COSMIC: COSV99430482;