rs141930814

Variant names:

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.5567G>A(p.Arg1856Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,756 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1856W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 32)

Exomes 𝑓: 0.014 ( 173 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.27

Publications

6 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=0.007861137).

BP6

Variant 2-151663744-C-T is Benign according to our data. Variant chr2-151663744-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129747.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 = 0.0104 (1581/152270) while in subpopulation NFE AF = 0.017 (1155/68020). AF 95% confidence interval is 0.0162. There are 14 homozygotes in GnomAd4. There are 755 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 45 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 45 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 45 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 45 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 45 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1582

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0114

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.0105

AC:

2621

AN:

248952

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.00473

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0141

AC:

20585

AN:

1461486

Hom.:

173

Cov.:

AF XY:

0.0139

AC XY:

10078

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33466

American (AMR)

AF:

0.00465

AC:

208

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00364

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00398

AC:

343

AN:

86254

European-Finnish (FIN)

AF:

0.0126

AC:

673

AN:

53380

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0166

AC:

18441

AN:

1111752

Other (OTH)

AF:

0.0123

AC:

740

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1238

2476

3714

4952

6190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.0104

AC:

1581

AN:

152270

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

755

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41558

American (AMR)

AF:

0.0107

AC:

163

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0114

AC:

121

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0170

AC:

1155

AN:

68020

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00934

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00326

AC:

ESP6500EA

AF:

0.0165

AC:

138

ExAC

AF:

0.0106

AC:

1281

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0151

EpiControl

AF:

0.0136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 08, 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. -

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 30, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Benign:3

Nov 28, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

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

MetaRNN

Benign

0.0079

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

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.1

M;M;.;M;M;M;M

PhyloP100

3.3

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.18

Sift

Benign

0.042

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

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;.;.

Vest4

0.35

MPC

0.18

ClinPred

0.040

GERP RS

5.5

Varity_R

0.24

gMVP

0.31

Mutation Taster

=100/0

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