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GeneBe

rs1429486273

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001164507.2(NEB):c.12977G>A(p.Arg4326His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4326C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 4)
Exomes 𝑓: 0.000010 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

1
1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -2.17
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31209314).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEBNM_001164507.2 linkuse as main transcriptc.12977G>A p.Arg4326His missense_variant 85/182 ENST00000427231.7
NEBNM_001164508.2 linkuse as main transcriptc.12977G>A p.Arg4326His missense_variant 85/182 ENST00000397345.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.12977G>A p.Arg4326His missense_variant 85/1825 NM_001164508.2 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.12977G>A p.Arg4326His missense_variant 85/1825 NM_001164507.2 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.11601+5167G>A intron_variant 5 P20929-4

Frequencies

GnomAD3 genomes
Cov.:
4
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000102
AC:
4
AN:
391224
Hom.:
0
Cov.:
0
AF XY:
0.0000195
AC XY:
4
AN XY:
205342
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:
0.000102
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 21, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
Cadd
Benign
12
Dann
Benign
0.94
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.036
N
LIST_S2
Benign
0.79
T;T;T;.;.
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.31
T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationTaster
Benign
1.0
N;N;N;N
PROVEAN
Benign
-1.2
N;.;N;.;.
REVEL
Benign
0.10
Sift
Uncertain
0.0040
D;.;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D
Vest4
0.18
MutPred
0.61
Loss of catalytic residue at R4326 (P = 0.0118);Loss of catalytic residue at R4326 (P = 0.0118);Loss of catalytic residue at R4326 (P = 0.0118);Loss of catalytic residue at R4326 (P = 0.0118);Loss of catalytic residue at R4326 (P = 0.0118);
MVP
0.72
MPC
0.34
ClinPred
0.55
D
GERP RS
0.72
gMVP
0.013

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.

Other links and lift over

dbSNP: rs1429486273; hg19: chr2-152461156; API