2-127063923-T-C

Variant names:

• chr2-127063923-T-C
• rs72481904
• NM_139343.3:c.698+10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139343.3(BIN1):​c.698+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,613,204 control chromosomes in the GnomAD database, including 105,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8320 hom., cov: 34)
  • Exomes 𝑓: 0.36 (96733 hom.)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.06
• Publications: 7 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-127063923-T-C is Benign according to our data. Variant chr2-127063923-T-C is described in ClinVar as Benign. ClinVar VariationId is 158017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.698+10A>G		intron_variant	Intron 8 of 18	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.698+10A>G		intron_variant	Intron 8 of 18	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47850 AN: 151986 Hom.: 8303 Cov.: 34

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.374 AC: 93983 AN: 251006 AF XY: 0.383

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.360 AC: 525349 AN: 1461098 Hom.: 96733 Cov.: 44 AF XY: 0.364 AC XY: 264810 AN XY: 726902

African (AFR) AF: 0.155 AC: 5189 AN: 33476

American (AMR) AF: 0.424 AC: 18939 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9094 AN: 26128

East Asian (EAS) AF: 0.352 AC: 13964 AN: 39692

South Asian (SAS) AF: 0.492 AC: 42428 AN: 86256

European-Finnish (FIN) AF: 0.365 AC: 19329 AN: 52900

Middle Eastern (MID) AF: 0.401 AC: 2314 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392441 AN: 1111786

Other (OTH) AF: 0.359 AC: 21651 AN: 60374

GnomAD4 genome AF: 0.315 AC: 47893 AN: 152106 Hom.: 8320 Cov.: 34 AF XY: 0.322 AC XY: 23960 AN XY: 74368

African (AFR) AF: 0.166 AC: 6880 AN: 41486

American (AMR) AF: 0.409 AC: 6256 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1276 AN: 3470

East Asian (EAS) AF: 0.392 AC: 2024 AN: 5162

South Asian (SAS) AF: 0.492 AC: 2378 AN: 4830

European-Finnish (FIN) AF: 0.353 AC: 3740 AN: 10580

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24032 AN: 67968

Other (OTH) AF: 0.351 AC: 742 AN: 2112

Alfa AF: 0.316 Hom.: 2456

Bravo AF: 0.309

Asia WGS AF: 0.430 AC: 1493 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 28, 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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

698+10A>G in intron 8 of BIN1: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 34.9% (3002/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs72481904). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Myopathy, centronuclear, 2 Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of 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: 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	-0.88
CADD	Benign	0.87
DANN	Benign	0.59
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs72481904; hg19: chr2-127821499; COSMIC: COSV52116919;