Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_139343.3(BIN1):c.1292C>T(p.Pro431Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,587,120 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P431S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00050 ( 7 hom. )

Consequence

BIN1
NM_139343.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.98

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

myopathy, centronuclear, 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
centronuclear myopathy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant centronuclear myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006077647).

BP6

Variant 2-127052334-G-A is Benign according to our data. Variant chr2-127052334-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00061 (93/152386) while in subpopulation EAS AF = 0.0173 (90/5190). AF 95% confidence interval is 0.0144. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BIN1	NM_139343.3	MANE Select	c.1292C>T	p.Pro431Leu	missense	Exon 15 of 19	NP_647593.1
BIN1	NM_001320642.1		c.1211C>T	p.Pro404Leu	missense	Exon 15 of 19	NP_001307571.1
BIN1	NM_001320641.2		c.1199C>T	p.Pro400Leu	missense	Exon 14 of 18	NP_001307570.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BIN1	ENST00000316724.10	TSL:1 MANE Select	c.1292C>T	p.Pro431Leu	missense	Exon 15 of 19	ENSP00000316779.5
BIN1	ENST00000357970.7	TSL:1	c.1163C>T	p.Pro388Leu	missense	Exon 14 of 18	ENSP00000350654.3
BIN1	ENST00000346226.7	TSL:1	c.1067C>T	p.Pro356Leu	missense	Exon 12 of 16	ENSP00000315411.3

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152268

Hom.:

Cov.:

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:

0.0173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00165

AC:

325

AN:

197520

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000240

Gnomad OTH exome

AF:

0.000589

GnomAD4 exome

AF:

0.000502

AC:

720

AN:

1434734

Hom.:

Cov.:

AF XY:

0.000460

AC XY:

327

AN XY:

711082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33090

American (AMR)

AF:

0.0000243

AC:

AN:

41148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25646

East Asian (EAS)

AF:

0.0172

AC:

662

AN:

38524

South Asian (SAS)

AF:

0.0000365

AC:

AN:

82282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50158

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

1099176

Other (OTH)

AF:

0.000540

AC:

AN:

59276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000610

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0173

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000421

Hom.:

Bravo

AF:

0.000990

ExAC

AF:

0.00110

AC:

131

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myopathy, centronuclear, 2 (2)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.11

Eigen_PC

Benign

0.047

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Benign

0.072

Sift4G

Benign

0.087

Polyphen

0.078

Vest4

0.32

MVP

0.77

MPC

0.29

ClinPred

0.095

GERP RS

3.8

Varity_R

0.073

gMVP

0.29

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs141119288

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over