rs2288200

Variant names:

• chr2-151547704-T-A
• rs2288200
• NM_001164507.2:c.20192A>T

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.20192A>T​(p.Asp6731Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,510 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D6731Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (404 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1033 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.67
• Publications: 10 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

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018514097).
• BP6: Variant 2-151547704-T-A is Benign according to our data. Variant chr2-151547704-T-A is described in ClinVar as Benign. ClinVar VariationId is 129721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20192A>T	p.Asp6731Val	missense_variant	Exon 132 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20192A>T	p.Asp6731Val	missense_variant	Exon 132 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20192A>T	p.Asp6731Val	missense_variant	Exon 132 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20192A>T	p.Asp6731Val	missense_variant	Exon 132 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6751 AN: 152096 Hom.: 392 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.0444

GnomAD2 exomes AF: 0.0305 AC: 7567 AN: 247902 AF XY: 0.0309

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0140 AC: 20443 AN: 1461296 Hom.: 1033 Cov.: 31 AF XY: 0.0154 AC XY: 11176 AN XY: 726914

African (AFR) AF: 0.127 AC: 4264 AN: 33450

American (AMR) AF: 0.00906 AC: 405 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 847 AN: 26126

East Asian (EAS) AF: 0.138 AC: 5457 AN: 39626

South Asian (SAS) AF: 0.0688 AC: 5929 AN: 86186

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53344

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5764

European-Non Finnish (NFE) AF: 0.00162 AC: 1796 AN: 1111736

Other (OTH) AF: 0.0269 AC: 1622 AN: 60350

GnomAD4 genome AF: 0.0446 AC: 6786 AN: 152214 Hom.: 404 Cov.: 31 AF XY: 0.0450 AC XY: 3352 AN XY: 74418

African (AFR) AF: 0.120 AC: 4975 AN: 41502

American (AMR) AF: 0.0194 AC: 297 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3470

East Asian (EAS) AF: 0.146 AC: 753 AN: 5170

South Asian (SAS) AF: 0.0780 AC: 376 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00223 AC: 152 AN: 68034

Other (OTH) AF: 0.0539 AC: 114 AN: 2116

Alfa AF: 0.0158 Hom.: 32

Bravo AF: 0.0486

TwinsUK AF: 0.000270 AC: 1

ESP6500AA AF: 0.118 AC: 446

ESP6500EA AF: 0.00314 AC: 26

ExAC AF: 0.0333 AC: 4018

Asia WGS AF: 0.137 AC: 474 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 14, 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.

Mar 04, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp6731Val in exon 132 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 11.8% (446/3794) of African Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2288200).

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Nemaline myopathy 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;T;.;D;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;.;.
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.;.;L;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D;D;.;D;D;D;.;.
Sift	Benign	0.063	T;D;.;D;T;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Vest4		0.84
ClinPred		0.016	T
GERP RS		5.9
Varity_R		0.53
gMVP		0.43
Mutation Taster		=100/0	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: rs2288200; hg19: chr2-152404218; COSMIC: COSV51419715;