rs6735208

Positions:

• chr2-151679984-T-A

Variant summary

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

The NM_001164508.2(NEB):​c.3081A>T​(p.Lys1027Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,612,454 control chromosomes in the GnomAD database, including 516,236 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (39583 hom., cov: 31)
  • Exomes 𝑓: 0.80 (476653 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.548

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=4.787806E-6).
• BP6: Variant 2-151679984-T-A is Benign according to our data. Variant chr2-151679984-T-A is described in ClinVar as [Benign]. Clinvar id is 95128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151679984-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3081A>T	p.Lys1027Asn	missense_variant	31/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3081A>T	p.Lys1027Asn	missense_variant	31/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3081A>T	p.Lys1027Asn	missense_variant	31/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.3081A>T	p.Lys1027Asn	missense_variant	31/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.3081A>T	p.Lys1027Asn	missense_variant	31/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105274 AN: 152000 Hom.: 39575 Cov.: 31

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.730

GnomAD3 exomes AF: 0.761 AC: 189525 AN: 249064 Hom.: 74923 AF XY: 0.762 AC XY: 102911 AN XY: 135114

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.736

Gnomad EAS exome AF: 0.487

Gnomad SAS exome AF: 0.643

Gnomad FIN exome AF: 0.859

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.801 AC: 1169316 AN: 1460336 Hom.: 476653 Cov.: 51 AF XY: 0.798 AC XY: 579485 AN XY: 726562

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.868

Gnomad4 ASJ exome AF: 0.738

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.654

Gnomad4 FIN exome AF: 0.859

Gnomad4 NFE exome AF: 0.836

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.692 AC: 105297 AN: 152118 Hom.: 39583 Cov.: 31 AF XY: 0.695 AC XY: 51713 AN XY: 74376

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.647

Gnomad4 FIN AF: 0.868

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.722

Alfa AF: 0.795 Hom.: 37006

Bravo AF: 0.678

TwinsUK AF: 0.841 AC: 3119

ALSPAC AF: 0.836 AC: 3221

ESP6500AA AF: 0.427 AC: 1662

ESP6500EA AF: 0.827 AC: 6827

ExAC AF: 0.749 AC: 90542

Asia WGS AF: 0.484 AC: 1689 AN: 3478

EpiCase AF: 0.839

EpiControl AF: 0.832

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.3081A) is the minor allele. This a llele (A) has been identified in 17% (1433/8260) of European American chromosome s and 57% (2230/3892) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs6735208) and thus meets criteria to be classified as benign. -
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. -

Nemaline myopathy 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.3081A>T (p.Lys1027Asn) variant involves the alteration of a non-conserved nucleotide, which 2/3 in silico tools (SNPs&GO not captured due to query not functioning and Mutation Taster having a low p-value) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.749942 (90494/120668 (35419 homozygotes)), which indicates that the T allele is the major allele found in the general population. In addition, multiple clinical diagnostic laboratories classify the variant as Benign. Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2019	- -

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	Benign	0.22
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;.;T;.;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.81	T;T;T;T;T;.;.
MetaRNN	Benign	0.0000048	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;L;L;L
MutationTaster	Benign	0.016	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;.;N;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.13	T;T;.;T;T;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.98	.;.;.;.;D;.;.
Vest4		0.14
MutPred		0.41		Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);Loss of methylation at K1027 (P = 0.0126);
MPC		0.093
ClinPred		0.036	T
GERP RS		-1.6
Varity_R		0.20
gMVP		0.37

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: rs6735208; hg19: chr2-152536498; COSMIC: COSV51419783;