rs2276579

chr2-127059056-G-Achr2-127059056-G-Cchr2-127059056-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_139343.3(BIN1):c.957C>T(p.Ala319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,576,122 control chromosomes in the GnomAD database, including 28,068 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. A319A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2027 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26041 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.500

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-127059056-G-A is Benign according to our data. Variant chr2-127059056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127059056-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.957C>T	p.Ala319=	synonymous_variant	11/19	ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.957C>T	p.Ala319=	synonymous_variant	11/19	1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21798 AN: 151992 Hom.: 2018 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.162 AC: 30419 AN: 188192 Hom.: 2729 AF XY: 0.163 AC XY: 16448 AN XY: 100884

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.0597

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.186 AC: 264790 AN: 1424012 Hom.: 26041 Cov.: 38 AF XY: 0.185 AC XY: 130316 AN XY: 704654

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.0385

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.143 AC: 21822 AN: 152110 Hom.: 2027 Cov.: 32 AF XY: 0.141 AC XY: 10502 AN XY: 74352

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.0483

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.176

Alfa AF: 0.138 Hom.: 375

Bravo AF: 0.143

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala319Ala in exon 11 of BIN1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 19.1% (1632/8532) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2276579). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Myopathy, centronuclear, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.5
Dann	Benign	0.48

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

LitVar

Other links and lift over

dbSNP: rs2276579; hg19: chr2-127816632; COSMIC: COSV52118503; COSMIC: COSV52118503;