rs1060743

Variant names:

• chr2-127068957-A-G
• rs1060743
• NM_139343.3:c.486T>C

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.486T>C​(p.Thr162Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,848 control chromosomes in the GnomAD database, including 79,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7058 hom., cov: 34)
  • Exomes 𝑓: 0.31 (72648 hom.)
• Consequence: BIN1 NM_139343.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.58

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=-0.81).
• BP6: Variant 2-127068957-A-G is Benign according to our data. Variant chr2-127068957-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127068957-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.486T>C	p.Thr162Thr	synonymous_variant	Exon 6 of 19	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.486T>C	p.Thr162Thr	synonymous_variant	Exon 6 of 19	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45238 AN: 152000 Hom.: 7047 Cov.: 34

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.337 AC: 84816 AN: 251346 Hom.: 14948 AF XY: 0.342 AC XY: 46419 AN XY: 135846

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.311 AC: 455011 AN: 1461728 Hom.: 72648 Cov.: 52 AF XY: 0.315 AC XY: 229265 AN XY: 727170

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.378

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.298 AC: 45280 AN: 152120 Hom.: 7058 Cov.: 34 AF XY: 0.303 AC XY: 22513 AN XY: 74374

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.300

Alfa AF: 0.304 Hom.: 15590

Bravo AF: 0.299

Asia WGS AF: 0.445 AC: 1546 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.299

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr162Thr in exon 6 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 29.0% (2498/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1060743). -

Myopathy, centronuclear, 2 Benign:3

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

- -

Jul 14, 2021

Genome-Nilou Lab

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	-0.81
CADD	Benign	0.062
DANN	Benign	0.52

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: rs1060743; hg19: chr2-127826533; COSMIC: COSV52118719; COSMIC: COSV52118719;