chr2-151579498-T-G

Position:

chr2-151579498-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164508.2(NEB):c.16544A>C(p.Lys5515Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,353,638 control chromosomes in the GnomAD database, including 59,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2913 hom., cov: 17)

Exomes 𝑓: 0.26 ( 59135 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.29

Variant links:

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]

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021787584).

BP6

Variant 2-151579498-T-G is Benign according to our data. Variant chr2-151579498-T-G is described in ClinVar as [Benign]. Clinvar id is 257764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151579498-T-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.16544A>C	p.Lys5515Thr	missense_variant	105/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.16544A>C	p.Lys5515Thr	missense_variant	105/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.16544A>C	p.Lys5515Thr	missense_variant	105/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.16544A>C	p.Lys5515Thr	missense_variant	105/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000413693.5 linkuse as main transcript	c.734A>C	p.Lys245Thr	missense_variant	5/74	5		ENSP00000410961.1	H0Y786
NEB	ENST00000409198.5 linkuse as main transcript	c.11602-3144A>C		intron_variant		5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

23044

AN:

122878

Hom.:

2916

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0640

Gnomad AMI

AF:

0.321

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.220

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.225

Gnomad MID

AF:

0.273

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.286

AC:

18868

AN:

66032

Hom.:

3243

AF XY:

0.285

AC XY:

9332

AN XY:

32714

show subpopulations

Gnomad AFR exome

AF:

0.0704

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.299

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.293

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.261

AC:

353794

AN:

1353638

Hom.:

59135

Cov.:

AF XY:

0.260

AC XY:

173664

AN XY:

668744

show subpopulations

Gnomad4 AFR exome

AF:

0.0708

Gnomad4 AMR exome

AF:

0.377

Gnomad4 ASJ exome

AF:

0.233

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.188

Gnomad4 FIN exome

AF:

0.301

Gnomad4 NFE exome

AF:

0.265

Gnomad4 OTH exome

AF:

0.258

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.187

AC:

23031

AN:

122966

Hom.:

2913

Cov.:

AF XY:

0.186

AC XY:

10817

AN XY:

58304

show subpopulations

Gnomad4 AFR

AF:

0.0639

Gnomad4 AMR

AF:

0.292

Gnomad4 ASJ

AF:

0.220

Gnomad4 EAS

AF:

0.268

Gnomad4 SAS

AF:

0.144

Gnomad4 FIN

AF:

0.225

Gnomad4 NFE

AF:

0.238

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.122

Hom.:

281

Bravo

AF:

0.221

ExAC

AF:

0.203

AC:

1260

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	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

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.034

.;T;.;T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

T;T;T;D;.;.

MetaRNN

Benign

0.0022

T;T;T;T;T;T

MetaSVM

Benign

-0.85

PROVEAN

Benign

-0.85

N;.;N;D;.;.

REVEL

Benign

0.12

Sift

Benign

0.035

D;.;D;D;.;.

Sift4G

Uncertain

0.030

D;D;D;D;D;D

Vest4

0.12

MPC

0.14

ClinPred

0.0052

GERP RS

3.6

gMVP

0.014

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over