2-151575797-T-C

Position:

• chr2-151575797-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.16911A>G​(p.Pro5637Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,576,262 control chromosomes in the GnomAD database, including 41,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3156 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38727 hom.)
• Consequence: NEB NM_001164508.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.245

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-151575797-T-C is Benign according to our data. Variant chr2-151575797-T-C is described in ClinVar as [Benign]. Clinvar id is 95106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151575797-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.245 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16911A>G	p.Pro5637Pro	splice_region_variant, synonymous_variant	107/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16911A>G	p.Pro5637Pro	splice_region_variant, synonymous_variant	107/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16911A>G	p.Pro5637Pro	splice_region_variant, synonymous_variant	107/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.16911A>G	p.Pro5637Pro	splice_region_variant, synonymous_variant	107/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11808A>G	p.Pro3936Pro	splice_region_variant, synonymous_variant	80/150	5		ENSP00000386259.1
NEB	ENST00000413693.5	c.1101A>G	p.Pro367Pro	splice_region_variant, synonymous_variant	7/74	5		ENSP00000410961.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26647 AN: 152122 Hom.: 3153 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.196 AC: 48787 AN: 248414 Hom.: 5826 AF XY: 0.206 AC XY: 27761 AN XY: 134804

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.000947

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.224 AC: 319001 AN: 1424022 Hom.: 38727 Cov.: 26 AF XY: 0.226 AC XY: 160918 AN XY: 710574

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.289

Gnomad4 EAS exome AF: 0.000758

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.175 AC: 26646 AN: 152240 Hom.: 3156 Cov.: 32 AF XY: 0.174 AC XY: 12966 AN XY: 74444

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.185

Alfa AF: 0.223 Hom.: 2794

Bravo AF: 0.158

Asia WGS AF: 0.0840 AC: 292 AN: 3478

EpiCase AF: 0.263

EpiControl AF: 0.262

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Pro5637Pro in exon 107 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 25% (2064/8154) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs33988153). -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 02, 2018	Variant summary: The NEB c.16911A>G (p.Pro5637Pro) variant involves the alteration of a non-conserved nucleotide located in a Nebulin repeat (IPR000900) (InterPro), resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 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 53815/276434 control chromosomes (6444 homozygotes) at a frequency of 0.1946758, which is approximately 55 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is 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 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	clinical testing	GeneDx	Jan 25, 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:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -

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	-0.53
CADD	Benign	5.6
DANN	Benign	0.61

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: rs33988153; hg19: chr2-152432311; COSMIC: COSV51417516;