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GeneBe

2-127048542-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_SupportingPP3

The NM_139343.3(BIN1):c.1766C>T(p.Thr589Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

3
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81

Links

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 33.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BIN1NM_139343.3 linkuse as main transcriptc.1766C>T p.Thr589Ile missense_variant 19/19 ENST00000316724.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.1766C>T p.Thr589Ile missense_variant 19/191 NM_139343.3 O00499-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250028
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135268
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000477
AC:
3
AN:
628562
Hom.:
0
AF XY:
0.00000876
AC XY:
3
AN XY:
342428
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:
0.00000857
Gnomad4 OTH exome
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 testingInvitaeJul 12, 2022This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 589 of the BIN1 protein (p.Thr589Ile). This variant is present in population databases (rs748600944, gnomAD 0.003%). 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: "Deleterious"; PolyPhen-2: "Probably 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
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Uncertain
25
Dann
Uncertain
1.0
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.89
T
MutationTaster
Benign
0.65
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.31
Sift
Benign
0.064
T;T;T;T;D;T;T;D;D;D;D
Sift4G
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;D;D;D;D;P;D;D;D;D;D
Vest4
0.73
MutPred
0.45
.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0301);.;
MVP
0.86
MPC
0.96
ClinPred
0.95
D
GERP RS
4.0
Varity_R
0.78
gMVP
0.71

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: rs748600944; hg19: chr2-127806118; API