rs12618063

Variant names:

• chr2-151675267-C-A
• rs12618063
• NM_001164507.2:c.3879+20G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151675267-C-A
• chr2-151675267-C-G

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.3879+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,502,142 control chromosomes in the GnomAD database, including 20,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3382 hom., cov: 32)
  • Exomes 𝑓: 0.13 (17442 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.371
• Publications: 8 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 (BayesDel_noAF=-0.86).
• BP6: Variant 2-151675267-C-A is Benign according to our data. Variant chr2-151675267-C-A is described in ClinVar as Benign. ClinVar VariationId is 167337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3879+20G>T		intron_variant	Intron 35 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3879+20G>T		intron_variant	Intron 35 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3879+20G>T		intron_variant	Intron 35 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3879+20G>T		intron_variant	Intron 35 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3879+20G>T		intron_variant	Intron 35 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27402 AN: 151932 Hom.: 3366 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.171 AC: 30628 AN: 179444 AF XY: 0.176

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.0861

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.134 AC: 181307 AN: 1350092 Hom.: 17442 Cov.: 25 AF XY: 0.138 AC XY: 92516 AN XY: 670062

African (AFR) AF: 0.315 AC: 9794 AN: 31054

American (AMR) AF: 0.0910 AC: 3381 AN: 37162

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3943 AN: 24958

East Asian (EAS) AF: 0.507 AC: 18916 AN: 37316

South Asian (SAS) AF: 0.277 AC: 21834 AN: 78786

European-Finnish (FIN) AF: 0.117 AC: 5951 AN: 50730

Middle Eastern (MID) AF: 0.148 AC: 831 AN: 5606

European-Non Finnish (NFE) AF: 0.105 AC: 107486 AN: 1027758

Other (OTH) AF: 0.162 AC: 9171 AN: 56722

GnomAD4 genome AF: 0.181 AC: 27466 AN: 152050 Hom.: 3382 Cov.: 32 AF XY: 0.182 AC XY: 13539 AN XY: 74330

African (AFR) AF: 0.302 AC: 12524 AN: 41418

American (AMR) AF: 0.109 AC: 1665 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3472

East Asian (EAS) AF: 0.490 AC: 2527 AN: 5158

South Asian (SAS) AF: 0.282 AC: 1357 AN: 4812

European-Finnish (FIN) AF: 0.110 AC: 1171 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7136 AN: 67984

Other (OTH) AF: 0.179 AC: 378 AN: 2114

Alfa AF: 0.145 Hom.: 473

Bravo AF: 0.184

Asia WGS AF: 0.424 AC: 1471 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Sep 25, 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.3879+20G>T variant involves the alteration of a non-conserved intronic nucleotide and 4/5 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 35623/207000 control chromosomes (109 homozygotes) at a frequency of 0.1720918, which is approximately 49 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -

Jan 28, 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. -

Nov 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:2

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.86
CADD	Benign	2.8
DANN	Benign	0.34
PhyloP100		-0.37
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: rs12618063; hg19: chr2-152531781; COSMIC: COSV51471194; COSMIC: COSV51471194;