rs115631125

Positions:

• chr2-151561253-C-A
• chr2-151561253-C-T

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.19056G>T​(p.Thr6352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,608,264 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (63 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.15

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=-0.77).
• BP6: Variant 2-151561253-C-A is Benign according to our data. Variant chr2-151561253-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151561253-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00395 (601/152260) while in subpopulation SAS AF= 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.19056G>T	p.Thr6352=	synonymous_variant	122/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.19056G>T	p.Thr6352=	synonymous_variant	122/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.19056G>T	p.Thr6352=	synonymous_variant	122/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.19056G>T	p.Thr6352=	synonymous_variant	122/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00575 AC: 1381 AN: 240254 Hom.: 13 AF XY: 0.00656 AC XY: 853 AN XY: 130022

Gnomad AFR exome AF: 0.000876

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00679

GnomAD4 exome AF: 0.00612 AC: 8913 AN: 1456004 Hom.: 63 Cov.: 31 AF XY: 0.00650 AC XY: 4705 AN XY: 723712

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00912

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00330

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74442

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00532

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00591 Hom.: 1

Bravo AF: 0.00389

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2017	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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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 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 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 provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NEB: BP4, BP7, BS1, BS2 -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.047
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs115631125; hg19: chr2-152417767;