chr2-151602679-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001164508.2(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. 11/17 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_001164508.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id is 227726.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=2}. Variant chr2-151602679-C-T is described in Lovd as [Benign].

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:

0.00

AC:

AN:

5074

Hom.:

Cov.:

FAILED QC

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

Gnomad4 AFR exome

AF:

0.00806

Gnomad4 AMR exome

AF:

0.000489

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000956

Gnomad4 SAS exome

AF:

0.000494

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00581

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000249

Gnomad4 OTH

AF:

0.00

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

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

Feb 15, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2020

GeneDx

Significance: Likely benign

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over