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GeneBe

2-127048537-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

The NM_139343.3(BIN1):c.1771A>G(p.Arg591Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R591R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

BIN1
NM_139343.3 missense

Scores

2
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Links

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 33.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.31287354).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BIN1NM_139343.3 linkuse as main transcriptc.1771A>G p.Arg591Gly missense_variant 19/19 ENST00000316724.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.1771A>G p.Arg591Gly missense_variant 19/191 NM_139343.3 O00499-1

Frequencies

GnomAD3 genomes
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myopathy, centronuclear, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 25, 2021This sequence change replaces arginine with glycine at codon 591 of the BIN1 protein (p.Arg591Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BIN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
Cadd
Benign
22
Dann
Uncertain
0.99
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.61
D
LIST_S2
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.010
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-4.6
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.021
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.18
B;P;B;B;P;B;B;B;P;B;B
Vest4
0.41
MutPred
0.42
.;.;.;.;.;.;.;.;.;Loss of solvent accessibility (P = 0.0807);.;
MVP
0.79
MPC
0.76
ClinPred
0.98
D
GERP RS
1.8
Varity_R
0.84
gMVP
0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-127806113; API