rs149025191

Positions:

Variant summary

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

The NM_001164507.2(NEB):c.11148G>C(p.Met3716Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,564,866 control chromosomes in the GnomAD database, including 269 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M3716T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 29 hom., cov: 31)

Exomes 𝑓: 0.016 ( 240 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.485

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=0.006017059).

BP6

Variant 2-151617397-C-G is Benign according to our data. Variant chr2-151617397-C-G is described in ClinVar as [Benign]. Clinvar id is 129706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151617397-C-G is described in Lovd as [Benign]. Variant chr2-151617397-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2035/149722) while in subpopulation NFE AF= 0.0185 (1257/67786). AF 95% confidence interval is 0.0177. There are 29 homozygotes in gnomad4. There are 1043 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.11148G>C	p.Met3716Ile	missense_variant	75/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.11148G>C	p.Met3716Ile	missense_variant	75/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.11148G>C	p.Met3716Ile	missense_variant	75/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.11148G>C	p.Met3716Ile	missense_variant	75/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.10419G>C	p.Met3473Ile	missense_variant	72/150	5			P20929-4
NEB	ENST00000486320.1 linkuse as main transcript	n.89G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2037

AN:

149610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.0144

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.00896

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0325

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0145

GnomAD3 exomes

AF:

0.0135

AC:

2609

AN:

192764

Hom.:

AF XY:

0.0143

AC XY:

1465

AN XY:

102778

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0000679

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.0162

AC:

22937

AN:

1415144

Hom.:

240

Cov.:

AF XY:

0.0162

AC XY:

11347

AN XY:

700108

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.00822

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.0156

Gnomad4 FIN exome

AF:

0.0303

Gnomad4 NFE exome

AF:

0.0171

Gnomad4 OTH exome

AF:

0.0147

GnomAD4 genome

AF:

0.0136

AC:

2035

AN:

149722

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1043

AN XY:

72936

show subpopulations

Gnomad4 AFR

AF:

0.00301

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.00896

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.0325

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.0143

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00346

AC:

ESP6500EA

AF:

0.0178

AC:

146

ExAC

AF:

0.00932

AC:

1106

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nemaline myopathy 2

Benign:3

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

.;.;T;.;T;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.87

D;T;T;T;D;.;.

MetaRNN

Benign

0.0060

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.33

N;.;.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

N;N;.;N;N;.;.

REVEL

Benign

0.11

Sift

Benign

0.41

T;T;.;T;T;.;.

Sift4G

Uncertain

0.049

D;T;T;T;D;T;T

Polyphen

0.060

.;.;.;.;B;.;.

Vest4

0.39

MutPred

0.52

Loss of ubiquitination at K3476 (P = 0.0957);.;.;.;Loss of ubiquitination at K3476 (P = 0.0957);.;.;

MPC

0.061

ClinPred

0.018

GERP RS

5.2

Varity_R

0.23

gMVP

0.11

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