2-151603657-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_001164507.2(NEB):c.13175G>A(p.Arg4392His) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 5.82

Publications

2 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2905161).

BP6

Variant 2-151603657-C-T is Benign according to our data. Variant chr2-151603657-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465473.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.13175G>A	p.Arg4392His	missense_variant	Exon 86 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.13175G>A	p.Arg4392His	missense_variant	Exon 86 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.13175G>A	p.Arg4392His	missense_variant	Exon 86 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.13175G>A	p.Arg4392His	missense_variant	Exon 86 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.11601+6152G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000721

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000227

AC:

AN:

154422

AF XY:

0.000183

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000539

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000480

AC:

670

AN:

1395414

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

335

AN XY:

688318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000639

AC:

AN:

31300

American (AMR)

AF:

0.000196

AC:

AN:

35670

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25178

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35734

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79134

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4060

European-Non Finnish (NFE)

AF:

0.000599

AC:

645

AN:

1077184

Other (OTH)

AF:

0.000190

AC:

AN:

57816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000369

AC:

AN:

151718

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74230

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000487

AC:

AN:

41070

American (AMR)

AF:

0.000261

AC:

AN:

15300

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:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000721

AC:

AN:

67928

Other (OTH)

AF:

0.000474

AC:

AN:

2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.268

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:

0.000751

Hom.:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nemaline myopathy 2

Uncertain:2

Jan 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.030

.;T;.;.;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D;D;.;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-1.2

PhyloP100

5.8

PROVEAN

Benign

-1.3

N;.;N;.;.

REVEL

Benign

0.11

Sift

Uncertain

0.0040

D;.;D;.;.

Sift4G

Uncertain

0.0060

D;D;D;D;D

Vest4

0.48

MutPred

0.45

Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);

MVP

0.56

MPC

0.34

ClinPred

0.18

GERP RS

3.1

gMVP

0.013

Mutation Taster

=93/7

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