rs149025191

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

nemaline myopathy 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.11148G>C	p.Met3716Ile	missense_variant	Exon 75 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.11148G>C	p.Met3716Ile	missense_variant	Exon 75 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.11148G>C	p.Met3716Ile	missense_variant	Exon 75 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.11148G>C	p.Met3716Ile	missense_variant	Exon 75 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.10419G>C	p.Met3473Ile	missense_variant	Exon 72 of 150	5		ENSP00000386259.1
NEB	ENST00000486320.1 link	n.89G>C		non_coding_transcript_exon_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.0135

AC:

2609

AN:

192764

AF XY:

0.0143

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 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

African (AFR)

AF:

0.00254

AC:

AN:

32710

American (AMR)

AF:

0.00822

AC:

322

AN:

39180

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

280

AN:

25334

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38152

South Asian (SAS)

AF:

0.0156

AC:

1267

AN:

81076

European-Finnish (FIN)

AF:

0.0303

AC:

1507

AN:

49740

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0171

AC:

18563

AN:

1084858

Other (OTH)

AF:

0.0147

AC:

856

AN:

58410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1016

2032

3049

4065

5081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0136

AC:

2035

AN:

149722

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1043

AN XY:

72936

show subpopulations

African (AFR)

AF:

0.00301

AC:

122

AN:

40540

American (AMR)

AF:

0.0127

AC:

190

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.00896

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.0145

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.0325

AC:

321

AN:

9862

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0185

AC:

1257

AN:

67786

Other (OTH)

AF:

0.0143

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.

PhyloP100

0.48

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

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over