2-127048534-C-A

Variant summary

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

The NM_139343.3(BIN1):​c.1774G>T​(p.Val592Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

12
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70
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.1774G>T p.Val592Phe missense_variant 19/19 ENST00000316724.10 NP_647593.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.1774G>T p.Val592Phe missense_variant 19/191 NM_139343.3 ENSP00000316779 O00499-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250144
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135326
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000718
AC:
105
AN:
1461646
Hom.:
0
Cov.:
31
AF XY:
0.0000509
AC XY:
37
AN XY:
727130
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000917
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

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 testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 592 of the BIN1 protein (p.Val592Phe). This variant is present in population databases (rs199908147, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BIN1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
Benign
0.19
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.32
.;.;.;.;.;.;.;.;.;T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Uncertain
0.60
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
1.7
.;.;.;.;.;.;.;.;.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;N;N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.2
N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.30
Sift
Uncertain
0.0080
D;D;D;D;D;D;T;T;T;T;T
Sift4G
Uncertain
0.010
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99
D;D;D;P;D;D;D;B;D;D;D
Vest4
0.67
MVP
0.89
MPC
1.0
ClinPred
0.75
D
GERP RS
4.0
Varity_R
0.14
gMVP
0.67

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: rs199908147; hg19: chr2-127806110; API