rs201962649

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001164507.2(NEB):c.17510A>G(p.Lys5837Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.93

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01410085).

BP6

Variant 2-151569293-T-C is Benign according to our data. Variant chr2-151569293-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465503.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152318) while in subpopulation AFR AF = 0.00339 (141/41570). AF 95% confidence interval is 0.00294. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.17510A>G	p.Lys5837Arg	missense_variant	Exon 110 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.17510A>G	p.Lys5837Arg	missense_variant	Exon 110 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.17510A>G	p.Lys5837Arg	missense_variant	Exon 110 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.17510A>G	p.Lys5837Arg	missense_variant	Exon 110 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.000972

AC:

148

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000225

AC:

AN:

249126

AF XY:

0.000215

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461608

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00352

AC:

118

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111796

Other (OTH)

AF:

0.000398

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000985

AC:

150

AN:

152318

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00339

AC:

141

AN:

41570

American (AMR)

AF:

0.000458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000420

Hom.:

Bravo

AF:

0.00116

ESP6500AA

AF:

0.00327

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000265

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Aug 26, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Benign:2

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEB-related disorder

Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

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

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.0072

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

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

PhyloP100

4.9

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

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

REVEL

Benign

0.14

Sift

Benign

0.12

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

Sift4G

Benign

0.36

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

Polyphen

0.0020

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

Vest4

0.34

MVP

0.56

MPC

0.055

ClinPred

0.023

GERP RS

6.1

Varity_R

0.24

gMVP

0.86

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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