rs145252235

chr2-151563847-C-T

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.18555G>A(p.Lys6185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,324 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 32)
  • Exomes 𝑓: 0.014 (200 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.21

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=-0.28).
• BP6: Variant 2-151563847-C-T is Benign according to our data. Variant chr2-151563847-C-T is described in ClinVar as [Benign]. Clinvar id is 129713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151563847-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0102 (1550/152312) while in subpopulation SAS AF= 0.0232 (112/4828). AF 95% confidence interval is 0.0197. There are 21 homozygotes in gnomad4. There are 744 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.18555G>A	p.Lys6185=	synonymous_variant	118/182	ENST00000427231.7
NEB	NM_001164508.2	c.18555G>A	p.Lys6185=	synonymous_variant	118/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.18555G>A	p.Lys6185=	synonymous_variant	118/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.18555G>A	p.Lys6185=	synonymous_variant	118/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1550 AN: 152194 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0118 AC: 2931 AN: 247856 Hom.: 29 AF XY: 0.0130 AC XY: 1748 AN XY: 134494

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00901

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0212

Gnomad FIN exome AF: 0.00279

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0146

GnomAD4 exome AF: 0.0139 AC: 20248 AN: 1461012 Hom.: 200 Cov.: 31 AF XY: 0.0143 AC XY: 10394 AN XY: 726794

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00940

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0102 AC: 1550 AN: 152312 Hom.: 21 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74472

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0127 Hom.: 7

Bravo AF: 0.0101

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2021	- -
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	GeneDx	Feb 29, 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:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	8.3
Dann	Benign	0.56

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: rs145252235; hg19: chr2-152420361;