2-127072643-A-C

Variant names:

• chr2-127072643-A-C
• rs17014873
• NM_139343.3:c.166-1827T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000316724.10(BIN1):​c.166-1827T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 151,746 control chromosomes in the GnomAD database, including 1,505 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1505 hom., cov: 32)
• Consequence: BIN1 ENST00000316724.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39
• Publications: 11 publications found

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]

BIN1 Gene-Disease associations (from GenCC):

• myopathy, centronuclear, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• centronuclear myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant centronuclear myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000316724.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.166-1827T>G		intron	N/A	NP_647593.1
	BIN1	NM_001320642.1		c.85-1827T>G		intron	N/A	NP_001307571.1
	BIN1	NM_001320641.2		c.166-1827T>G		intron	N/A	NP_001307570.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.166-1827T>G		intron	N/A	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.166-1827T>G		intron	N/A	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.166-1827T>G		intron	N/A	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16770 AN: 151628 Hom.: 1498 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0858

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.111 AC: 16801 AN: 151746 Hom.: 1505 Cov.: 32 AF XY: 0.108 AC XY: 7990 AN XY: 74176

African (AFR) AF: 0.244 AC: 10052 AN: 41230

American (AMR) AF: 0.0523 AC: 798 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5164

South Asian (SAS) AF: 0.119 AC: 573 AN: 4798

European-Finnish (FIN) AF: 0.0523 AC: 551 AN: 10538

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4490 AN: 67962

Other (OTH) AF: 0.0849 AC: 179 AN: 2108

Alfa AF: 0.0791 Hom.: 568

Bravo AF: 0.116

Asia WGS AF: 0.0900 AC: 315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.6
DANN	Benign	0.53
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17014873; hg19: chr2-127830219;