rs2288210

Variant names:

• chr2-151565562-C-G
• rs2288210
• NM_001164507.2:c.18305G>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.18305G>C​(p.Arg6102Thr) variant causes a missense change. The variant allele was found at a frequency of 0.667 in 1,593,254 control chromosomes in the GnomAD database, including 357,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R6102I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (33628 hom., cov: 33)
  • Exomes 𝑓: 0.67 (323622 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.83
• Publications: 27 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=1.4958271E-6).
• BP6: Variant 2-151565562-C-G is Benign according to our data. Variant chr2-151565562-C-G is described in ClinVar as Benign. ClinVar VariationId is 95109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18305G>C	p.Arg6102Thr	missense_variant	Exon 116 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18305G>C	p.Arg6102Thr	missense_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.18305G>C	p.Arg6102Thr	missense_variant	Exon 116 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18305G>C	p.Arg6102Thr	missense_variant	Exon 116 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100598 AN: 152024 Hom.: 33579 Cov.: 33

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.667 AC: 161643 AN: 242204 AF XY: 0.657

Gnomad AFR exome AF: 0.617

Gnomad AMR exome AF: 0.765

Gnomad ASJ exome AF: 0.566

Gnomad EAS exome AF: 0.793

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.667 AC: 961578 AN: 1441112 Hom.: 323622 Cov.: 36 AF XY: 0.662 AC XY: 475064 AN XY: 717328

African (AFR) AF: 0.624 AC: 20755 AN: 33270

American (AMR) AF: 0.759 AC: 33280 AN: 43872

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14700 AN: 25978

East Asian (EAS) AF: 0.821 AC: 32447 AN: 39498

South Asian (SAS) AF: 0.534 AC: 45574 AN: 85348

European-Finnish (FIN) AF: 0.695 AC: 36978 AN: 53178

Middle Eastern (MID) AF: 0.635 AC: 3638 AN: 5728

European-Non Finnish (NFE) AF: 0.671 AC: 734540 AN: 1094496

Other (OTH) AF: 0.664 AC: 39666 AN: 59744

GnomAD4 genome AF: 0.662 AC: 100708 AN: 152142 Hom.: 33628 Cov.: 33 AF XY: 0.665 AC XY: 49454 AN XY: 74382

African (AFR) AF: 0.619 AC: 25671 AN: 41492

American (AMR) AF: 0.738 AC: 11282 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1959 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4102 AN: 5180

South Asian (SAS) AF: 0.547 AC: 2633 AN: 4816

European-Finnish (FIN) AF: 0.701 AC: 7422 AN: 10584

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45562 AN: 68004

Other (OTH) AF: 0.671 AC: 1418 AN: 2114

Alfa AF: 0.668 Hom.: 25707

Bravo AF: 0.666

TwinsUK AF: 0.676 AC: 2507

ALSPAC AF: 0.667 AC: 2570

ESP6500AA AF: 0.620 AC: 2280

ESP6500EA AF: 0.663 AC: 5438

ExAC AF: 0.657 AC: 79232

Asia WGS AF: 0.678 AC: 2358 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

This is a RefSeq error. The reference base (c.18305G) is the minor allele. This allele (G) has been identified in 34% (2760/8198) of European American chromosom es and 38% (1400/3680) of African American chromosomes by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2288210) and thus meets criteria to be classified as benign. -

-

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. -

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:4

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

- -

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.18305G>C (p.Arg6102Thr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 75124/112008 control chromosomes (24879 homozygotes) at a frequency of 0.6707021, which is approximately 190 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in a patient affected with muscular dystrophy for which a spicing variant in CHKB likely can explain the phenoytpe. This variant has also been reported in an acral melanoma sample witout evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely 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
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.49
DEOGEN2	Benign	0.0031	.;.;T;.;T;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.14	T;T;T;T;T;T;.;.
MetaRNN	Benign	0.0000015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	N;.;.;.;N;.;.;.
PhyloP100		5.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.4	N;N;.;N;N;N;.;.
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T;.;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.;.
Vest4		0.13
MPC		0.070
ClinPred		0.0088	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.23
Mutation Taster		=99/1	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: rs2288210; hg19: chr2-152422076; COSMIC: COSV51426817;