rs587783346

Positions:

• chr2-127059167-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139343.3(BIN1):​c.858-12C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,564,704 control chromosomes in the GnomAD database, including 29,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3166 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26706 hom.)
• Consequence: BIN1 NM_139343.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001381
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0720

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-127059167-G-T is Benign according to our data. Variant chr2-127059167-G-T is described in ClinVar as [Benign]. Clinvar id is 158020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127059167-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.858-12C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.858-12C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30211 AN: 151654 Hom.: 3162 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.176 AC: 30060 AN: 170668 Hom.: 2786 AF XY: 0.179 AC XY: 16337 AN XY: 91240

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.193 AC: 272036 AN: 1412932 Hom.: 26706 Cov.: 42 AF XY: 0.191 AC XY: 133556 AN XY: 698274

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.199 AC: 30236 AN: 151772 Hom.: 3166 Cov.: 31 AF XY: 0.198 AC XY: 14707 AN XY: 74164

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.160

Alfa AF: 0.188 Hom.: 584

Bravo AF: 0.192

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	858-12C>A in intron 10 of BIN1: This variant is not expected to have clinical si gnificance because it has been identified in 22.3% (978/4376) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs6720741). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Myopathy, centronuclear, 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.098
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: rs6720741; hg19: chr2-127816743;