NM_001164507.2:c.3147+5G>A

Variant names:

• chr2-151679913-C-T
• rs74859201
• NM_001164507.2:c.3147+5G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.3147+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,610,910 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 31)
  • Exomes 𝑓: 0.017 (275 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.05

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 2-151679913-C-T is Benign according to our data. Variant chr2-151679913-C-T is described in ClinVar as [Benign]. Clinvar id is 129739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151679913-C-T is described in Lovd as [Likely_benign]. Variant chr2-151679913-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0128 (1957/152300) while in subpopulation SAS AF= 0.0247 (119/4826). AF 95% confidence interval is 0.0211. There are 23 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3147+5G>A		splice_region_variant, intron_variant	Intron 31 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3147+5G>A		splice_region_variant, intron_variant	Intron 31 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3147+5G>A		splice_region_variant, intron_variant	Intron 31 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3147+5G>A		splice_region_variant, intron_variant	Intron 31 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3147+5G>A		splice_region_variant, intron_variant	Intron 31 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1952 AN: 152182 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0161 AC: 4012 AN: 249134 Hom.: 44 AF XY: 0.0174 AC XY: 2355 AN XY: 135150

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00418

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0171 AC: 24882 AN: 1458610 Hom.: 275 Cov.: 32 AF XY: 0.0176 AC XY: 12810 AN XY: 725834

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.0470

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.0300

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0128 AC: 1957 AN: 152300 Hom.: 23 Cov.: 31 AF XY: 0.0128 AC XY: 952 AN XY: 74478

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0430

Gnomad4 EAS AF: 0.00462

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0174 Hom.: 29

Bravo AF: 0.0116

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.0180

EpiControl AF: 0.0203

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.3147+5G>A in intron 31 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 1.9% (160/8370) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs74859201). -

Apr 01, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.3147+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes and two predict the variant weakens the 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 120684 control chromosomes in the ExAC database, including 17 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3147+5G>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Mar 12, 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. -

Oct 20, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Nov 28, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

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
BayesDel_noAF	Benign	-0.76
CADD	Uncertain	24
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74859201; hg19: chr2-152536427;