chr2-127052264-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_139343.3(BIN1):c.1362G>T(p.Gly454Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,572,668 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G454G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 40 hom., cov: 34)

Exomes 𝑓: 0.023 ( 454 hom. )

Consequence

BIN1
NM_139343.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.197

Publications

10 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-127052264-C-A is Benign according to our data. Variant chr2-127052264-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.197 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3 link	c.1362G>T	p.Gly454Gly	synonymous_variant	Exon 15 of 19	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.1362G>T	p.Gly454Gly	synonymous_variant	Exon 15 of 19	1	NM_139343.3	ENSP00000316779.5		O00499-1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2442

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00446

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0490

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0203

AC:

3632

AN:

178980

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00926

Gnomad ASJ exome

AF:

0.00890

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.0226

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0229

AC:

32552

AN:

1420316

Hom.:

454

Cov.:

AF XY:

0.0241

AC XY:

16959

AN XY:

702538

show subpopulations

African (AFR)

AF:

0.00294

AC:

AN:

32692

American (AMR)

AF:

0.00947

AC:

371

AN:

39182

Ashkenazi Jewish (ASJ)

AF:

0.00815

AC:

207

AN:

25400

East Asian (EAS)

AF:

0.0000798

AC:

AN:

37586

South Asian (SAS)

AF:

0.0517

AC:

4176

AN:

80784

European-Finnish (FIN)

AF:

0.0166

AC:

828

AN:

49814

Middle Eastern (MID)

AF:

0.0285

AC:

159

AN:

5584

European-Non Finnish (NFE)

AF:

0.0234

AC:

25476

AN:

1090576

Other (OTH)

AF:

0.0211

AC:

1236

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1743

3486

5229

6972

8715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<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:

0.0160

AC:

2441

AN:

152352

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1243

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41582

American (AMR)

AF:

0.0150

AC:

230

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0493

AC:

238

AN:

4830

European-Finnish (FIN)

AF:

0.0176

AC:

187

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0222

AC:

1510

AN:

68030

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0147

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.0230

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2016

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. -

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, centronuclear, 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.6

(source)

DANN

Benign

0.72

PhyloP100

0.20

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