2-151565051-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.18464A>C (p.Tyr6155Ser) variant in NEB is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 6155. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.004863 (391/73822 alleles, 3 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.271, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1907955/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:8

Conservation

PhyloP100: 2.72

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: Likely_benign. The variant received -4 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.18464A>C	p.Tyr6155Ser	missense_variant	Exon 117 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.18464A>C	p.Tyr6155Ser	missense_variant	Exon 117 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.18464A>C	p.Tyr6155Ser	missense_variant	Exon 117 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.18464A>C	p.Tyr6155Ser	missense_variant	Exon 117 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000387

AC:

AN:

240502

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.00588

Gnomad AMR exome

AF:

0.0000895

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000134

AC:

189

AN:

1405964

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

701476

show subpopulations

African (AFR)

AF:

0.00546

AC:

176

AN:

32240

American (AMR)

AF:

0.0000456

AC:

AN:

43822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25640

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.00

AC:

AN:

82952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065052

Other (OTH)

AF:

0.000188

AC:

AN:

58466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00144

AC:

220

AN:

152344

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00517

AC:

215

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000649

Hom.:

Bravo

AF:

0.00162

ESP6500AA

AF:

0.00575

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000456

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 11, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline myopathy 2

Benign:2

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 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.

Inborn genetic diseases

Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.13361A>C (p.Y4454S) alteration is located in exon 90 (coding exon 88) of the NEB gene. This alteration results from a A to C substitution at nucleotide position 13361, causing the tyrosine (Y) at amino acid position 4454 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Limb-girdle muscular dystrophy

Uncertain:1

Sep 03, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jun 12, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB-related disorder

Benign:1

May 29, 2019

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).

Nemaline myopathy

Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.18464A>C (p.Tyr6155Ser) variant in NEB is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 6155. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.004863 (391/73822 alleles, 3 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.271, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.4

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

PhyloP100

2.7

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

N;D;.;D;N;D;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.016

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

Sift4G

Uncertain

0.016

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

Vest4

0.58

ClinPred

0.041

GERP RS

6.0

Varity_R

0.18

gMVP

0.52

Mutation Taster

=99/1

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