rs1553466026

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139343.3(BIN1):ā€‹c.469T>Cā€‹(p.Tyr157His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

14
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.28
Variant links:
Genes affected
BIN1 (HGNC:1052): (bridging integrator 1) This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in several transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described. [provided by RefSeq, Mar 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BIN1NM_139343.3 linkuse as main transcriptc.469T>C p.Tyr157His missense_variant 6/19 ENST00000316724.10 NP_647593.1 O00499-1A0A024RAF1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.469T>C p.Tyr157His missense_variant 6/191 NM_139343.3 ENSP00000316779.5 O00499-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461846
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 12, 2019Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Myopathy, centronuclear, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 08, 2017This sequence change replaces tyrosine with histidine at codon 157 of the BIN1 protein (p.Tyr157His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BIN1-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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.0065
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
.;.;.;.;.;.;.;.;.;D;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.087
D
MetaRNN
Uncertain
0.64
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.8
L;L;L;L;L;L;L;L;L;L;L
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.97
D;D;D;P;D;D;D;D;P;P;P
Vest4
0.46
MutPred
0.73
Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);
MVP
0.83
MPC
1.9
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.40
gMVP
0.66

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: rs1553466026; hg19: chr2-127826550; API