rs10172023

chr2-151619514-C-Gchr2-151619514-C-T

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.10809G>C(p.Trp3603Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,274 control chromosomes in the GnomAD database, including 80,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W3603R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5713 hom., cov: 32)
  • Exomes 𝑓: 0.32 (74739 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.22

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=0.0016649961).
• BP6: Variant 2-151619514-C-G is Benign according to our data. Variant chr2-151619514-C-G is described in ClinVar as [Benign]. Clinvar id is 95102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151619514-C-G is described in Lovd as [Benign]. Variant chr2-151619514-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.10809G>C	p.Trp3603Cys	missense_variant	73/182	ENST00000427231.7
NEB	NM_001164508.2	c.10809G>C	p.Trp3603Cys	missense_variant	73/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.10809G>C	p.Trp3603Cys	missense_variant	73/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.10809G>C	p.Trp3603Cys	missense_variant	73/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.10080G>C	p.Trp3360Cys	missense_variant	70/150	5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39871 AN: 151940 Hom.: 5709 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.292 AC: 72637 AN: 248552 Hom.: 11133 AF XY: 0.290 AC XY: 39028 AN XY: 134792

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.263

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.315 AC: 460833 AN: 1461216 Hom.: 74739 Cov.: 40 AF XY: 0.312 AC XY: 226923 AN XY: 726800

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.262 AC: 39883 AN: 152058 Hom.: 5713 Cov.: 32 AF XY: 0.263 AC XY: 19565 AN XY: 74308

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.258

Alfa AF: 0.312 Hom.: 5653

Bravo AF: 0.253

TwinsUK AF: 0.340 AC: 1262

ALSPAC AF: 0.338 AC: 1301

ESP6500AA AF: 0.139 AC: 564

ESP6500EA AF: 0.331 AC: 2784

ExAC AF: 0.288 AC: 34864

Asia WGS AF: 0.233 AC: 811 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.312

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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)	May 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Trp3603Cys in exon 73 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 33% (2784/8400) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs10172023). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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:5

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 24, 2017

Variant summary: The NEB c.10809G>C (p.Trp3603Cys) variant involves the alteration of a non-conserved nucleotide and 3/3 in silico tools (SNPsandGo and Mutation Taster not captured here due to low reliability index and p-value, respectively) predict a damaging outcome. This variant was found in 34849/120540 control chromosomes (5272 homozygotes) at a frequency of 0.2891074, which is approximately 82 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Therefore, the variant of interest has been classified as Benign. -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.065	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M;.;.;.;M;.;.
MutationTaster	Benign	1.1e-7	P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.2	D;D;.;D;D;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.68
MutPred		0.58		Loss of catalytic residue at W3360 (P = 0.0794);.;.;.;Loss of catalytic residue at W3360 (P = 0.0794);.;.;
MPC		0.42
ClinPred		0.016	T
GERP RS		5.6
Varity_R		0.59
gMVP		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: rs10172023; hg19: chr2-152476028; COSMIC: COSV51216946; COSMIC: COSV51216946;