chr2-151602679-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001164507.2(NEB):c.13276G>A(p.Asp4426Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.00039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000089 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.70

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21040237).

BP6

Variant 2-151602679-C-T is Benign according to our data. Variant chr2-151602679-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227726.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.13276G>A	p.Asp4426Asn	missense_variant	Exon 87 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.13276G>A	p.Asp4426Asn	missense_variant	Exon 87 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.13276G>A	p.Asp4426Asn	missense_variant	Exon 87 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.13276G>A	p.Asp4426Asn	missense_variant	Exon 87 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+7130G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

5074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00581

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:

0.000249

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000889

AC:

AN:

67488

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

35698

show subpopulations

African (AFR)

AF:

0.00806

AC:

AN:

124

American (AMR)

AF:

0.000489

AC:

AN:

2044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

884

East Asian (EAS)

AF:

0.000956

AC:

AN:

1046

South Asian (SAS)

AF:

0.000494

AC:

AN:

4048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.0000214

AC:

AN:

46822

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000394

AC:

AN:

5076

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

AN XY:

2314

show subpopulations

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

African (AFR)

AF:

0.00581

AC:

AN:

172

American (AMR)

AF:

0.00

AC:

AN:

312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

100

East Asian (EAS)

AF:

0.00

AC:

AN:

104

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000249

AC:

AN:

4016

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ 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: 0.225

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:

0.000769

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Sep 17, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 82, 90, and 98) are co-amplified and sequenced (each amplicon consists of 6 a lleles). This variant represents a nonhomologous position within the three repet itive blocks (c.13276G, c.14734A, and c.16192G). The variable alleles at this po sition are not expected to have clinical significance due to a lack of conservat ion at this position across species, including mammals. A change at this positio n has also been identified in 0.4% (41/10774) to 15% (3900/21678) of chromosomes across several diverse populations by the Exome Aggregate Consortium (http://ex ac.broadinstitute.org/). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Uncertain

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0038

.;T;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.15

T;T;T;.;.

M_CAP

Benign

0.047

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.7

PROVEAN

Benign

-0.30

N;.;N;.;.

REVEL

Benign

0.040

Sift

Uncertain

0.011

D;.;D;.;.

Sift4G

Uncertain

0.010

D;D;D;D;D

Vest4

0.16

MutPred

0.33

Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);

MVP

0.56

MPC

0.31

ClinPred

0.21

GERP RS

3.5

gMVP

0.0081

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