rs10909569

chr2-151592126-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.14734A>G(p.Asn4912Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,198,524 control chromosomes in the GnomAD database, including 1,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (73 hom., cov: 30)
  • Exomes 𝑓: 0.087 (995 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.844

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003677845).
• BP6: Variant 2-151592126-T-C is Benign according to our data. Variant chr2-151592126-T-C is described in ClinVar as [Benign]. Clinvar id is 257743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151592126-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.14734A>G	p.Asn4912Asp	missense_variant	95/182	ENST00000427231.7
NEB	NM_001164508.2	c.14734A>G	p.Asn4912Asp	missense_variant	95/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.14734A>G	p.Asn4912Asp	missense_variant	95/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.14734A>G	p.Asn4912Asp	missense_variant	95/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11602-15772A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.115 AC: 13447 AN: 116724 Hom.: 73 Cov.: 30

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.0365

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0881

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.0868 AC: 93853 AN: 1081670 Hom.: 995 Cov.: 35 AF XY: 0.0882 AC XY: 47045 AN XY: 533108

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.0973

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0669

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.0842

Gnomad4 OTH exome AF: 0.0942

GnomAD4 genome AF: 0.115 AC: 13451 AN: 116854 Hom.: 73 Cov.: 30 AF XY: 0.114 AC XY: 6498 AN XY: 57190

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0917

Gnomad4 EAS AF: 0.0996

Gnomad4 SAS AF: 0.0884

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.121

Alfa AF: 0.195 Hom.: 14

ExAC AF: 0.150 AC: 3745

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	15
Dann	Benign	0.94
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.076	T;T;T;.;.
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	0.12	N;.;N;.;.
REVEL	Benign	0.029
Sift	Benign	0.21	T;.;T;.;.
Sift4G	Benign	0.44	T;T;T;T;T
Vest4		0.044
MPC		0.057
ClinPred		0.0028	T
GERP RS		2.6
gMVP		0.0069

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: rs10909569; hg19: chr2-152448640; COSMIC: COSV50847635;