2-127050470-T-C

Position:

chr2-127050470-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_139343.3(BIN1):c.1625A>G(p.Lys542Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,222 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0079 ( 3 hom., cov: 34)

Exomes 𝑓: 0.011 ( 133 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.03

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]

BIN1 links:

BIN1 (HGNC:):

BIN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0087840855).

BP6

Variant 2-127050470-T-C is Benign according to our data. Variant chr2-127050470-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158011.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=7}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00794 (1210/152346) while in subpopulation NFE AF= 0.0131 (893/68022). AF 95% confidence interval is 0.0124. There are 3 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIN1	NM_139343.3 linkuse as main transcript	c.1625A>G	p.Lys542Arg	missense_variant	18/19	ENST00000316724.10	NP_647593.1	O00499-1A0A024RAF1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10 linkuse as main transcript	c.1625A>G	p.Lys542Arg	missense_variant	18/19	1	NM_139343.3	ENSP00000316779.5		O00499-1

Frequencies

GnomAD3 genomes

AF:

0.00794

AC:

1209

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00925

AC:

2325

AN:

251424

Hom.:

AF XY:

0.00909

AC XY:

1236

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.00864

GnomAD4 exome

AF:

0.0109

AC:

15980

AN:

1461876

Hom.:

133

Cov.:

AF XY:

0.0106

AC XY:

7683

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.0142

Gnomad4 NFE exome

AF:

0.0130

Gnomad4 OTH exome

AF:

0.00897

GnomAD4 genome

AF:

0.00794

AC:

1210

AN:

152346

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

579

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0148

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00710

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.0127

AC:

109

ExAC

AF:

0.0112

AC:

1360

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2020	- -

Myopathy, centronuclear, 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

BIN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.64

T;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0088

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.0

.;.;.;.;.;.;.;.;.;L;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.7

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.082

T;D;T;T;D;T;T;D;T;D;T

Sift4G

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.99

D;P;B;D;B;P;B;B;D;B;D

Vest4

0.18

MPC

0.69

ClinPred

0.021

GERP RS

4.6

Varity_R

0.41

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over