chr2-127050540-C-G

Variant names:

• chr2-127050540-C-G
• rs12466912
• NM_139343.3:c.1573-18G>C

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.1573-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,712 control chromosomes in the GnomAD database, including 2,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (344 hom., cov: 34)
  • Exomes 𝑓: 0.037 (2479 hom.)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.32

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=-1.02).
• BP6: Variant 2-127050540-C-G is Benign according to our data. Variant chr2-127050540-C-G is described in ClinVar as [Benign]. Clinvar id is 262474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127050540-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.1573-18G>C		intron_variant	Intron 17 of 18	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.1573-18G>C		intron_variant	Intron 17 of 18	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7562 AN: 152226 Hom.: 343 Cov.: 34

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0754 AC: 18920 AN: 250800 Hom.: 1309 AF XY: 0.0725 AC XY: 9832 AN XY: 135652

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.0883

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0373 AC: 54474 AN: 1461368 Hom.: 2479 Cov.: 32 AF XY: 0.0391 AC XY: 28406 AN XY: 727046

Gnomad4 AFR exome AF: 0.0396

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.0388

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0497 AC: 7570 AN: 152344 Hom.: 344 Cov.: 34 AF XY: 0.0563 AC XY: 4195 AN XY: 74494

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0907

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0179 Hom.: 15

Bravo AF: 0.0514

Asia WGS AF: 0.147 AC: 511 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myopathy, centronuclear, 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.38

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: rs12466912; hg19: chr2-127808116; COSMIC: COSV52118920;