rs886038439

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001164508.2(NEB):c.13680G>C(p.Gln4560His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: not found (cov: 0)

Exomes 𝑓: 0.00026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164508.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.62

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 -1 ACMG points.

BP6

Variant 2-151600550-C-G is Benign according to our data. Variant chr2-151600550-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.13680G>C	p.Gln4560His	missense_variant	Exon 89 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.13680G>C	p.Gln4560His	missense_variant	Exon 89 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.13680G>C	p.Gln4560His	missense_variant	Exon 89 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.13680G>C	p.Gln4560His	missense_variant	Exon 89 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+9259G>C		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000263

AC:

AN:

7594

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

AN XY:

4072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000520

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1

Sep 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with histidine at codon 4560 of the NEB protein (p.Gln4560His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This variant is not present in the population databases and has not been reported in the literature in individuals with NEB-related disease. However, it occurs in the triplicated region of NEB and the frequency data is considered unreliable. Algorithms developed to predict the effect of missense changes on protein structure and function are not able to calculate the potential effect of amino acid changes in this region. In summary, this variant is a novel missense change with an uncertain impact on protein function. Missense variants in the NEB gene are typically not pathogenic, and there is no indication that this variant causes disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Apr 14, 2021

GeneDx

Significance: Likely 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

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.35

DEOGEN2

Benign

0.019

.;T;.;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D;.;.

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.43

T;T;T;T;T

MetaSVM

Benign

-0.41

PROVEAN

Benign

-0.56

N;.;N;.;.

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.44

MutPred

0.61

Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);

MVP

0.48

MPC

0.13

ClinPred

0.18

GERP RS

2.5

gMVP

0.012

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

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