rs13427102

Positions:

• chr2-151680837-C-T

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.2944-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,592,550 control chromosomes in the GnomAD database, including 5,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (974 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4575 hom.)
• Consequence: NEB NM_001164507.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003707
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.09

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=-0.9).
• BP6: Variant 2-151680837-C-T is Benign according to our data. Variant chr2-151680837-C-T is described in ClinVar as [Benign]. Clinvar id is 129738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.2944-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.2944-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.2944-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.2944-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.2944-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15107 AN: 151898 Hom.: 973 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0659

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0490

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0829

GnomAD3 exomes AF: 0.0706 AC: 17580 AN: 248918 Hom.: 797 AF XY: 0.0695 AC XY: 9390 AN XY: 135022

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0447

Gnomad SAS exome AF: 0.0692

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0739

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0758 AC: 109156 AN: 1440534 Hom.: 4575 Cov.: 28 AF XY: 0.0752 AC XY: 54022 AN XY: 718066

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0517

Gnomad4 SAS exome AF: 0.0672

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0766

Gnomad4 OTH exome AF: 0.0818

GnomAD4 genome AF: 0.0995 AC: 15126 AN: 152016 Hom.: 974 Cov.: 32 AF XY: 0.0958 AC XY: 7121 AN XY: 74330

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0658

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.0665

Gnomad4 FIN AF: 0.0253

Gnomad4 NFE AF: 0.0761

Gnomad4 OTH AF: 0.0821

Alfa AF: 0.0973 Hom.: 258

Bravo AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.2944-9G>A in intron 29 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 16.9% (626/3704) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs13427102). -

Nemaline myopathy 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.2944-9G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 8961/120726 control chromosomes (433 homozygotes) at a frequency of 0.0742259, which is approximately 21 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/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.90
CADD	Benign	2.6
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0040
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: rs13427102; hg19: chr2-152537351; COSMIC: COSV51444142;