rs12618063

chr2-151675267-C-Achr2-151675267-C-G

Variant summary

Our verdict is Benign. Variant got -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:7
• Conservation: PhyloP100: -0.371

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 167337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151675267-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NEB	NM_001164507.2	c.3879+20G>T		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.3879+20G>T		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.3879+20G>T		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.3879+20G>T		intron_variant		5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.3879+20G>T		intron_variant		5

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

GnomAD3 exomes AF: 0.171 AC: 30628 AN: 179444 Hom.: 3790 AF XY: 0.176 AC XY: 16593 AN XY: 94432

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 SAS exome AF: 0.284

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

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.0910

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.162

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

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.179

Alfa AF: 0.141 Hom.: 440

Bravo AF: 0.184

Asia WGS AF: 0.424 AC: 1471 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2016	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.8
Dann	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs12618063; hg19: chr2-152531781; COSMIC: COSV51471194; COSMIC: COSV51471194;