NM_001164507.2:c.6175G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001164507.2(NEB):c.6175G>A(p.Ala2059Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,603,152 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 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:3

Conservation

PhyloP100: 4.86

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 -1 ACMG points.

BP6

Variant 2-151657991-C-T is Benign according to our data. Variant chr2-151657991-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534007.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.6175G>A	p.Ala2059Thr	missense_variant	Exon 48 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.6175G>A	p.Ala2059Thr	missense_variant	Exon 48 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.6175G>A	p.Ala2059Thr	missense_variant	Exon 48 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.6175G>A	p.Ala2059Thr	missense_variant	Exon 48 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.6175G>A	p.Ala2059Thr	missense_variant	Exon 48 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000220

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000903

AC:

AN:

243512

AF XY:

0.0000834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

156

AN:

1450850

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

721808

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33208

American (AMR)

AF:

0.000203

AC:

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000128

AC:

141

AN:

1103766

Other (OTH)

AF:

0.000100

AC:

AN:

59958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.000125

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41584

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.000135

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEB-related disorder

Uncertain:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NEB c.6175G>A variant is predicted to result in the amino acid substitution p.Ala2059Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

See cases

Benign:1

Dec 16, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2, BP1, BP4 -

Nemaline myopathy 2

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.61

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

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.8

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

PhyloP100

4.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.26

Sift

Uncertain

0.010

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.98

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

Vest4

0.83

MVP

0.61

MPC

0.33

ClinPred

0.28

GERP RS

5.9

Varity_R

0.24

gMVP

0.46

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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