rs114076205

chr2-151684781-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.2832C>T(p.Ser944=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,587,170 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.23

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=-0.62).
• BP6: Variant 2-151684781-G-A is Benign according to our data. Variant chr2-151684781-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 167340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151684781-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00703 (1070/152272) while in subpopulation NFE AF= 0.0111 (754/68026). AF 95% confidence interval is 0.0104. There are 4 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.2832C>T	p.Ser944=	synonymous_variant	28/182	ENST00000427231.7
NEB	NM_001164508.2	c.2832C>T	p.Ser944=	synonymous_variant	28/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.2832C>T	p.Ser944=	synonymous_variant	28/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.2832C>T	p.Ser944=	synonymous_variant	28/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.2832C>T	p.Ser944=	synonymous_variant	28/150	5

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1072 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00708 AC: 1647 AN: 232524 Hom.: 9 AF XY: 0.00753 AC XY: 947 AN XY: 125766

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00510

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00644

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.0105 AC: 15098 AN: 1434898 Hom.: 92 Cov.: 30 AF XY: 0.0105 AC XY: 7454 AN XY: 710816

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00500

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00642

Gnomad4 FIN exome AF: 0.00535

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00880

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74442

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00876 Hom.: 4

Bravo AF: 0.00712

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

Nemaline myopathy 2 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

NEB: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.41
Dann	Benign	0.41

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: rs114076205; hg19: chr2-152541295;