rs139963368

Positions:

• chr2-151662303-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001164507.2(NEB):​c.5802C>T​(p.Gly1934=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,506 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.603

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-151662303-G-A is Benign according to our data. Variant chr2-151662303-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.603 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0053 (807/152194) while in subpopulation AFR AF= 0.0144 (600/41544). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.5802C>T	p.Gly1934=	synonymous_variant	46/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.5802C>T	p.Gly1934=	synonymous_variant	46/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.5802C>T	p.Gly1934=	synonymous_variant	46/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.5802C>T	p.Gly1934=	synonymous_variant	46/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.5802C>T	p.Gly1934=	synonymous_variant	46/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152076 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00238 AC: 593 AN: 248804 Hom.: 2 AF XY: 0.00228 AC XY: 308 AN XY: 134952

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00249

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00148 AC: 2166 AN: 1461312 Hom.: 12 Cov.: 31 AF XY: 0.00146 AC XY: 1058 AN XY: 726938

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000983

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00530 AC: 807 AN: 152194 Hom.: 6 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74414

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00281 Hom.: 3

Bravo AF: 0.00583

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.4
DANN	Benign	0.62

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: rs139963368; hg19: chr2-152518817;