rs1137845

chr2-127063631-G-A

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.714C>T(p.Tyr238=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,613,502 control chromosomes in the GnomAD database, including 3,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (350 hom., cov: 33)
  • Exomes 𝑓: 0.045 (3058 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.07

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=-0.77).
• BP6: Variant 2-127063631-G-A is Benign according to our data. Variant chr2-127063631-G-A is described in ClinVar as [Benign]. Clinvar id is 158018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127063631-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.714C>T	p.Tyr238=	synonymous_variant	9/19	ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.714C>T	p.Tyr238=	synonymous_variant	9/19	1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7396 AN: 152130 Hom.: 351 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0919

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0823 AC: 20566 AN: 249820 Hom.: 1440 AF XY: 0.0813 AC XY: 10991 AN XY: 135218

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0532

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.0890

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0592

GnomAD4 exome AF: 0.0450 AC: 65730 AN: 1461254 Hom.: 3058 Cov.: 33 AF XY: 0.0476 AC XY: 34608 AN XY: 726918

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0846

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0476

GnomAD4 genome AF: 0.0486 AC: 7402 AN: 152248 Hom.: 350 Cov.: 33 AF XY: 0.0559 AC XY: 4159 AN XY: 74426

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0919

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0373 Hom.: 194

Bravo AF: 0.0487

Asia WGS AF: 0.159 AC: 551 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Tyr238Tyr in exon 9 of BIN1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 2.9% (248/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs1137845). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Myopathy, centronuclear, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.14
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1137845; hg19: chr2-127821207; COSMIC: COSV52116899;