NM_001164507.2:c.12905A>T

Variant names:

Variant summary

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

The NM_001164507.2(NEB):c.12905A>T(p.Asn4302Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00026 ( 0 hom., cov: 5)

Exomes 𝑓: 0.0020 ( 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:2

Conservation

PhyloP100: -1.31

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=0.20436049).

BP6

Variant 2-151604714-T-A is Benign according to our data. Variant chr2-151604714-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr2-151604714-T-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12905A>T	p.Asn4302Ile	missense_variant	Exon 85 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12905A>T	p.Asn4302Ile	missense_variant	Exon 85 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12905A>T	p.Asn4302Ile	missense_variant	Exon 85 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12905A>T	p.Asn4302Ile	missense_variant	Exon 85 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+5095A>T		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

30424

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000414

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:

0.000404

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000460

AC:

AN:

50012

Hom.:

AF XY:

0.000513

AC XY:

AN XY:

25364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000175

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000988

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00204

AC:

833

AN:

408430

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

426

AN XY:

214994

show subpopulations

Gnomad4 AFR exome

AF:

0.000558

Gnomad4 AMR exome

AF:

0.000727

Gnomad4 ASJ exome

AF:

0.000552

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00191

Gnomad4 FIN exome

AF:

0.00209

Gnomad4 NFE exome

AF:

0.00252

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000263

AC:

AN:

30434

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

AN XY:

13588

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000413

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000404

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000789

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Nov 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with isoleucine at codon 4302 of the NEB protein (p.Asn4302Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. 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. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "probably damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with 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. -

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Mar 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25205138) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.35

DANN

Benign

0.89

DEOGEN2

Benign

0.030

.;T;.;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.57

T;T;T;.;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-2.0

N;.;N;.;.

REVEL

Benign

0.086

Sift

Uncertain

0.012

D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.45

MutPred

0.53

Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);Gain of catalytic residue at P4304 (P = 0.0298);

MVP

0.44

MPC

0.36

ClinPred

0.085

GERP RS

0.67

gMVP

0.0017

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