2-151633722-C-T

Position:

chr2-151633722-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.9346G>A(p.Glu3116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,984 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 13 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0300

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=0.011828959).

BP6

Variant 2-151633722-C-T is Benign according to our data. Variant chr2-151633722-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151633722-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00171 (2495/1461688) while in subpopulation MID AF= 0.0052 (30/5768). AF 95% confidence interval is 0.00374. There are 13 homozygotes in gnomad4_exome. There are 1326 alleles in male gnomad4_exome subpopulation. Median coverage is 115. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.9346G>A	p.Glu3116Lys	missense_variant	65/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.9346G>A	p.Glu3116Lys	missense_variant	65/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.9346G>A	p.Glu3116Lys	missense_variant	65/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.9346G>A	p.Glu3116Lys	missense_variant	65/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.8854-2544G>A		intron_variant		5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00212

AC:

527

AN:

249118

Hom.:

AF XY:

0.00218

AC XY:

294

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.000696

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00171

AC:

2495

AN:

1461688

Hom.:

Cov.:

115

AF XY:

0.00182

AC XY:

1326

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00262

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00139

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152296

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00251

AC:

ExAC

AF:

0.00220

AC:

266

EpiCase

AF:

0.00316

EpiControl

AF:

0.00285

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NEB: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.5

DANN

Benign

0.97

DEOGEN2

Benign

0.017

.;T;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.87

D;T;D;.;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;N;N

PROVEAN

Benign

-0.69

N;.;N;.;.

REVEL

Benign

0.13

Sift

Benign

0.57

T;.;T;.;.

Sift4G

Uncertain

0.028

D;D;D;D;D

Vest4

0.29

MVP

0.43

MPC

0.057

ClinPred

0.023

GERP RS

0.66

gMVP

0.047

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