rs140186806

Variant names:

• chr2-151658007-C-T
• rs140186806
• NM_001164507.2:c.6159G>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_001164508.2(NEB):​c.6159G>A​(p.Lys2053Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00916 in 1,609,240 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (75 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0320

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=-0.49).
• BP6: Variant 2-151658007-C-T is Benign according to our data. Variant chr2-151658007-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.032 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00845 (1286/152268) while in subpopulation AMR AF= 0.0143 (218/15264). AF 95% confidence interval is 0.0127. There are 5 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.6159G>A	p.Lys2053Lys	synonymous_variant	Exon 48 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6159G>A	p.Lys2053Lys	synonymous_variant	Exon 48 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6159G>A	p.Lys2053Lys	synonymous_variant	Exon 48 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.6159G>A	p.Lys2053Lys	synonymous_variant	Exon 48 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.6159G>A	p.Lys2053Lys	synonymous_variant	Exon 48 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152150 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00780 AC: 1915 AN: 245622 Hom.: 12 AF XY: 0.00808 AC XY: 1076 AN XY: 133152

Gnomad AFR exome AF: 0.00230

Gnomad AMR exome AF: 0.00778

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.00276

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00923 AC: 13449 AN: 1456972 Hom.: 75 Cov.: 30 AF XY: 0.00921 AC XY: 6677 AN XY: 724694

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00335

Gnomad4 FIN exome AF: 0.00314

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.00845 AC: 1286 AN: 152268 Hom.: 5 Cov.: 32 AF XY: 0.00791 AC XY: 589 AN XY: 74428

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0108 Hom.: 6

Bravo AF: 0.00876

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 22, 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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB: BP4, BP7, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.49
CADD	Benign	3.5
DANN	Benign	0.64

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: rs140186806; hg19: chr2-152514521;