rs115350357

Variant names:

• chr2-151658000-T-C
• rs115350357
• NM_001164507.2:c.6166A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.6166A>G	p.Arg2056Gly	missense	Exon 48 of 150	ENSP00000386259.1

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

GnomAD2 exomes AF: 0.000873 AC: 214 AN: 245020 AF XY: 0.000632

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 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

African (AFR) AF: 0.0113 AC: 377 AN: 33286

American (AMR) AF: 0.000744 AC: 33 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85496

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53162

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1107332

Other (OTH) AF: 0.00106 AC: 64 AN: 60104

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

African (AFR) AF: 0.0120 AC: 498 AN: 41570

American (AMR) AF: 0.00196 AC: 30 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00115 Hom.: 1

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

Dec 09, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB-related disorder Benign:1

Mar 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Nov 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.50	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Benign	0.046	D
Sift4G	Uncertain	0.027	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
Mutation Taster		=70/30	polymorphism

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