rs2288211

Variant names:

• chr2-151565573-A-G
• rs2288211
• NM_001164507.2:c.18294T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164507.2(NEB):​c.18294T>C​(p.Tyr6098Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,590,154 control chromosomes in the GnomAD database, including 69,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5698 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63957 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.35
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-151565573-A-G is Benign according to our data. Variant chr2-151565573-A-G is described in ClinVar as Benign. ClinVar VariationId is 95108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	Exon 116 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	Exon 116 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	Exon 116 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18294T>C	p.Tyr6098Tyr	synonymous_variant	Exon 116 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38006 AN: 152078 Hom.: 5701 Cov.: 32

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.287 AC: 69058 AN: 240454 AF XY: 0.283

Gnomad AFR exome AF: 0.0816

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.291 AC: 419159 AN: 1437958 Hom.: 63957 Cov.: 31 AF XY: 0.289 AC XY: 207051 AN XY: 715828

African (AFR) AF: 0.0775 AC: 2579 AN: 33262

American (AMR) AF: 0.402 AC: 17518 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6638 AN: 25980

East Asian (EAS) AF: 0.346 AC: 13647 AN: 39448

South Asian (SAS) AF: 0.197 AC: 16796 AN: 85170

European-Finnish (FIN) AF: 0.311 AC: 16503 AN: 53120

Middle Eastern (MID) AF: 0.278 AC: 1591 AN: 5730

European-Non Finnish (NFE) AF: 0.299 AC: 326842 AN: 1092054

Other (OTH) AF: 0.286 AC: 17045 AN: 59596

GnomAD4 genome AF: 0.250 AC: 38005 AN: 152196 Hom.: 5698 Cov.: 32 AF XY: 0.252 AC XY: 18753 AN XY: 74426

African (AFR) AF: 0.0873 AC: 3627 AN: 41552

American (AMR) AF: 0.392 AC: 5996 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3472

East Asian (EAS) AF: 0.321 AC: 1660 AN: 5174

South Asian (SAS) AF: 0.198 AC: 956 AN: 4826

European-Finnish (FIN) AF: 0.297 AC: 3138 AN: 10582

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20745 AN: 67988

Other (OTH) AF: 0.268 AC: 568 AN: 2116

Alfa AF: 0.286 Hom.: 19998

Bravo AF: 0.252

Asia WGS AF: 0.214 AC: 749 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.Tyr6098Tyr in exon 116 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 29% (2380/8182) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2288211). -

Nov 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 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. -

Nemaline myopathy 2 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

-

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.18294T>C (p.Tyr6098Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 30819/104302 control chromosomes (4493 homozygotes) at a frequency of 0.2954785, which is approximately 84 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.6
DANN	Benign	0.61
PhyloP100		1.3
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: rs2288211; hg19: chr2-152422087; COSMIC: COSV50873501;