2-151633944-A-G

Variant names:

• chr2-151633944-A-G
• rs6710212
• NM_001164507.2:c.9124T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.9124T>C​(p.Cys3042Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,354 control chromosomes in the GnomAD database, including 800,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C3042H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.98 (72814 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727493 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.10
• Publications: 24 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=8.425502E-7).
• BP6: Variant 2-151633944-A-G is Benign according to our data. Variant chr2-151633944-A-G is described in ClinVar as Benign. ClinVar VariationId is 226847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.9124T>C	p.Cys3042Arg	missense	Exon 65 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.9124T>C	p.Cys3042Arg	missense	Exon 65 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.9124T>C	p.Cys3042Arg	missense	Exon 65 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.9124T>C	p.Cys3042Arg	missense	Exon 65 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9124T>C	p.Cys3042Arg	missense	Exon 65 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.8854-2766T>C		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148679 AN: 152164 Hom.: 72757 Cov.: 31

Gnomad AFR AF: 0.920

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.994 AC: 247644 AN: 249042 AF XY: 0.996

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1457917 AN: 1461072 Hom.: 727493 Cov.: 70 AF XY: 0.998 AC XY: 725414 AN XY: 726706

African (AFR) AF: 0.922 AC: 30822 AN: 33436

American (AMR) AF: 0.996 AC: 44524 AN: 44692

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26130 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39686

South Asian (SAS) AF: 1.00 AC: 86245 AN: 86254

European-Finnish (FIN) AF: 1.00 AC: 53384 AN: 53400

Middle Eastern (MID) AF: 0.998 AC: 5757 AN: 5766

European-Non Finnish (NFE) AF: 1.00 AC: 1111254 AN: 1111358

Other (OTH) AF: 0.996 AC: 60116 AN: 60350

GnomAD4 genome AF: 0.977 AC: 148796 AN: 152282 Hom.: 72814 Cov.: 31 AF XY: 0.978 AC XY: 72830 AN XY: 74458

African (AFR) AF: 0.920 AC: 38209 AN: 41532

American (AMR) AF: 0.992 AC: 15175 AN: 15296

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4818 AN: 4818

European-Finnish (FIN) AF: 0.999 AC: 10621 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68023 AN: 68036

Other (OTH) AF: 0.990 AC: 2094 AN: 2116

Alfa AF: 0.992 Hom.: 110949

Bravo AF: 0.974

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.922 AC: 1276

ESP6500EA AF: 0.999 AC: 3179

ExAC AF: 0.993 AC: 119921

Asia WGS AF: 0.997 AC: 3468 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Dec 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.9124T) is the minor allele. This a llele (T) has been identified in 7.8% (108/1384) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs6710212) and thus meets criteria to be classified as benign.

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 27, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NEB c.9124T>C (p.Cys3042Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 119893/120760 control chromosomes (59546 homozygotes) at a frequency of 0.9928205, which is approximately 281 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is the dominant allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Mar 04, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nemaline myopathy 2 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.1
PROVEAN	Benign	3.3	N
REVEL	Benign	0.13
Sift	Benign	0.97	T
Sift4G	Benign	1.0	T
Vest4		0.16
MPC		0.083
ClinPred		0.020	T
GERP RS		6.0
gMVP		0.040
Mutation Taster		=98/2	polymorphism (auto)

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: rs6710212; hg19: chr2-152490458; COSMIC: COSV107246878;