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GeneBe

2-127048530-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139343.3(BIN1):c.1778C>T(p.Pro593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

2
3
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18247545).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BIN1NM_139343.3 linkuse as main transcriptc.1778C>T p.Pro593Leu missense_variant 19/19 ENST00000316724.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BIN1ENST00000316724.10 linkuse as main transcriptc.1778C>T p.Pro593Leu missense_variant 19/191 NM_139343.3 O00499-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250228
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135362
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:
0.00000616
AC:
9
AN:
1461602
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727098
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:
0.00000719
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

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 testingRevvity Omics, RevvityDec 16, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.33
Cadd
Benign
18
Dann
Uncertain
0.99
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.37
N
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.18
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
0.98
N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.17
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D;B;D;D
Vest4
0.30
MVP
0.63
MPC
0.93
ClinPred
0.62
D
GERP RS
2.5
Varity_R
0.11
gMVP
0.23

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: rs375004668; hg19: chr2-127806106; API