dbSNP rs78967885: BIN1:c.1263+11C>T (chr2-127053411-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_139343.3(BIN1):c.1263+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00909 in 1,613,860 control chromosomes in the GnomAD database, including 88 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 0.0088 ( 9 hom., cov: 34)

Exomes 𝑓: 0.0091 ( 79 hom. )

Consequence

BIN1
NM_139343.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.429

Publications

1 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):

centronuclear myopathy
Inheritance: AD, AR, SD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
myopathy, centronuclear, 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-127053411-G-A is Benign according to our data. Variant chr2-127053411-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210527.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00881 (1342/152334) while in subpopulation NFE AF = 0.0121 (822/68022). AF 95% confidence interval is 0.0114. There are 9 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 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	Effect	Exon Rank	Protein	UniProt
BIN1	NM_139343.3	MANE Select	c.1263+11C>T	intron	N/A	NP_647593.1	O00499-1
BIN1	NM_001320642.1		c.1182+11C>T	intron	N/A	NP_001307571.1	O00499
BIN1	NM_001320641.2		c.1170+11C>T	intron	N/A	NP_001307570.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BIN1	ENST00000316724.10	TSL:1 MANE Select	c.1263+11C>T	intron	N/A	ENSP00000316779.5	O00499-1
BIN1	ENST00000357970.7	TSL:1	c.1134+11C>T	intron	N/A	ENSP00000350654.3	O00499-5
BIN1	ENST00000346226.7	TSL:1	c.1039-1049C>T	intron	N/A	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes

AF:

0.00882

AC:

1343

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00825

AC:

2065

AN:

250272

AF XY:

0.00785

show subpopulations

Gnomad AFR exome

AF:

0.00633

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00687

GnomAD4 exome

AF:

0.00912

AC:

13334

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

6417

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.00538

AC:

180

AN:

33472

American (AMR)

AF:

0.00217

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26130

East Asian (EAS)

AF:

0.000176

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.0180

AC:

963

AN:

53368

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0104

AC:

11605

AN:

1111848

Other (OTH)

AF:

0.00737

AC:

445

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

756

1512

2268

3024

3780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.00881

AC:

1342

AN:

152334

Hom.:

Cov.:

AF XY:

0.00918

AC XY:

684

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00568

AC:

236

AN:

41580

American (AMR)

AF:

0.00255

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0189

AC:

201

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0121

AC:

822

AN:

68022

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00903

Hom.:

Bravo

AF:

0.00756

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Myopathy, centronuclear, 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.97

(source)

DANN

Benign

0.47

PhyloP100

-0.43

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

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

Computational scores

Splicing

Publications

Other links and lift over