rs115350357

chr2-151658000-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):c.6166A>G(p.Arg2056Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,607,390 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009800762).
• BP6: Variant 2-151658000-T-C is Benign according to our data. Variant chr2-151658000-T-C is described in ClinVar as [Benign]. Clinvar id is 387292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00357 (543/152256) while in subpopulation AFR AF= 0.012 (498/41570). AF 95% confidence interval is 0.0111. There are 2 homozygotes in gnomad4. There are 280 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.6166A>G	p.Arg2056Gly	missense_variant	48/182	ENST00000427231.7
NEB	NM_001164508.2	c.6166A>G	p.Arg2056Gly	missense_variant	48/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.6166A>G	p.Arg2056Gly	missense_variant	48/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.6166A>G	p.Arg2056Gly	missense_variant	48/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.6166A>G	p.Arg2056Gly	missense_variant	48/150	5

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000873 AC: 214 AN: 245020 Hom.: 0 AF XY: 0.000632 AC XY: 84 AN XY: 132814

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000501

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000341 AC: 496 AN: 1455134 Hom.: 1 Cov.: 30 AF XY: 0.000298 AC XY: 216 AN XY: 723832

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000744

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152256 Hom.: 2 Cov.: 32 AF XY: 0.00376 AC XY: 280 AN XY: 74448

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000650 Hom.: 0

Bravo AF: 0.00422

ESP6500AA AF: 0.00995 AC: 37

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -

NEB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.50	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
MetaRNN	Benign	0.0098	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.8	M;M;.;M;M;M;M
MutationTaster	Benign	0.85	D;D;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;.;.
REVEL	Benign	0.28
Sift	Benign	0.046	D;T;.;T;D;.;.
Sift4G	Uncertain	0.027	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.
Vest4		0.77
MVP		0.52
MPC		0.36
ClinPred		0.036	T
GERP RS		2.1
Varity_R		0.33
gMVP		0.52

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: rs115350357; hg19: chr2-152514514; COSMIC: COSV51471169;