rs34555492

chr2-151540718-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164507.2(NEB):c.20766C>T(p.Asp6922=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,436 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.020 (377 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.22

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-151540718-G-A is Benign according to our data. Variant chr2-151540718-G-A is described in ClinVar as [Benign]. Clinvar id is 129723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151540718-G-A is described in Lovd as [Likely_benign]. Variant chr2-151540718-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0131 (1997/152210) while in subpopulation SAS AF= 0.038 (183/4820). AF 95% confidence interval is 0.0335. There are 23 homozygotes in gnomad4. There are 928 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	ENST00000427231.7
NEB	NM_001164508.2	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	ENST00000397345.8
LOC124906081	XR_007087266.1	n.2943G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20766C>T	p.Asp6922=	synonymous_variant	137/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152092 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0154 AC: 3840 AN: 248722 Hom.: 63 AF XY: 0.0174 AC XY: 2346 AN XY: 134906

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.00539

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0201 AC: 29301 AN: 1461226 Hom.: 377 Cov.: 31 AF XY: 0.0206 AC XY: 14997 AN XY: 726904

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0397

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152210 Hom.: 23 Cov.: 32 AF XY: 0.0125 AC XY: 928 AN XY: 74418

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0380

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0166 Hom.: 11

Bravo AF: 0.0120

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	-	- -
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	Apr 22, 2019	Variant summary: NEB c.20766C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.015 in 280110 control chromosomes in the gnomAD database, including 68 homozygotes. The observed variant frequency is approximately 4-folds higher than 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 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	-0.75
Cadd	Benign	0.052
Dann	Benign	0.49

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: rs34555492; hg19: chr2-152397232;