2-127082205-C-A

Variant names:

• chr2-127082205-C-A
• rs10194375
• NM_139343.3:c.85-5499G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_139343.3(BIN1):​c.85-5499G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 151,680 control chromosomes in the GnomAD database, including 7,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7639 hom., cov: 30)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 33 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):

• centronuclear myopathy

  Inheritance: AD, AR, SD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• myopathy, centronuclear, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-127082205-C-A is Benign according to our data. Variant chr2-127082205-C-A is described in ClinVar as Benign. ClinVar VariationId is 1251745.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.85-5499G>T		intron	N/A	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.3+1384G>T		intron	N/A	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.85-5499G>T		intron	N/A	NP_001307570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.85-5499G>T		intron	N/A	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.85-5499G>T		intron	N/A	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.85-5499G>T		intron	N/A	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47389 AN: 151562 Hom.: 7628 Cov.: 30

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.313 AC: 47449 AN: 151680 Hom.: 7639 Cov.: 30 AF XY: 0.314 AC XY: 23272 AN XY: 74096

African (AFR) AF: 0.261 AC: 10791 AN: 41400

American (AMR) AF: 0.308 AC: 4708 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1108 AN: 3462

East Asian (EAS) AF: 0.198 AC: 1017 AN: 5130

South Asian (SAS) AF: 0.297 AC: 1416 AN: 4760

European-Finnish (FIN) AF: 0.389 AC: 4104 AN: 10560

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23190 AN: 67788

Other (OTH) AF: 0.293 AC: 619 AN: 2110

Alfa AF: 0.328 Hom.: 24140

Bravo AF: 0.301

Asia WGS AF: 0.300 AC: 1043 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.89
DANN	Benign	0.79
PhyloP100		-1.5
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: rs10194375; hg19: chr2-127839781;