chr2-127069056-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_139343.3(BIN1):c.412-25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,608,512 control chromosomes in the GnomAD database, including 86,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.33 ( 8602 hom., cov: 33)

Exomes 𝑓: 0.32 ( 78146 hom. )

Consequence

BIN1
NM_139343.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.796

Publications

9 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-127069056-A-G is Benign according to our data. Variant chr2-127069056-A-G is described in ClinVar as Benign. ClinVar VariationId is 678128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3 link	c.412-25T>C		intron_variant	Intron 5 of 18	ENST00000316724.10	NP_647593.1	O00499-1A0A024RAF1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10 link	c.412-25T>C		intron_variant	Intron 5 of 18	1	NM_139343.3	ENSP00000316779.5		O00499-1

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50157

AN:

151948

Hom.:

8591

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.0952

Gnomad SAS

AF:

0.397

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.325

Gnomad OTH

AF:

0.291

GnomAD2 exomes

AF:

0.300

AC:

74848

AN:

249172

AF XY:

0.309

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.180

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.323

AC:

470415

AN:

1456446

Hom.:

78146

Cov.:

AF XY:

0.324

AC XY:

235113

AN XY:

724820

show subpopulations

African (AFR)

AF:

0.406

AC:

13540

AN:

33380

American (AMR)

AF:

0.182

AC:

8138

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

6751

AN:

26080

East Asian (EAS)

AF:

0.0879

AC:

3485

AN:

39660

South Asian (SAS)

AF:

0.405

AC:

34916

AN:

86184

European-Finnish (FIN)

AF:

0.336

AC:

17645

AN:

52548

Middle Eastern (MID)

AF:

0.321

AC:

1847

AN:

5754

European-Non Finnish (NFE)

AF:

0.330

AC:

365233

AN:

1107968

Other (OTH)

AF:

0.313

AC:

18860

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

17298

34597

51895

69194

86492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11804

23608

35412

47216

59020

<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:

0.330

AC:

50203

AN:

152066

Hom.:

8602

Cov.:

AF XY:

0.329

AC XY:

24453

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.402

AC:

16685

AN:

41500

American (AMR)

AF:

0.230

AC:

3508

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

924

AN:

3468

East Asian (EAS)

AF:

0.0960

AC:

496

AN:

5168

South Asian (SAS)

AF:

0.396

AC:

1909

AN:

4822

European-Finnish (FIN)

AF:

0.336

AC:

3555

AN:

10582

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.325

AC:

22083

AN:

67934

Other (OTH)

AF:

0.295

AC:

623

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1735

3470

5204

6939

8674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.320

Hom.:

3163

Bravo

AF:

0.317

Asia WGS

AF:

0.258

AC:

900

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Myopathy, centronuclear, 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

0.80

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over