chr2-127058848-A-G

Variant names:

• chr2-127058848-A-G
• rs2276582
• NM_139343.3:c.1002+163T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139343.3(BIN1):​c.1002+163T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 152,070 control chromosomes in the GnomAD database, including 22,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.53 (22965 hom., cov: 33)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0420
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-127058848-A-G is Benign according to our data. Variant chr2-127058848-A-G is described in ClinVar as Benign. ClinVar VariationId is 678144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 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.1002+163T>C		intron	N/A	NP_647593.1
	BIN1	NM_001320642.1		c.921+163T>C		intron	N/A	NP_001307571.1
	BIN1	NM_001320641.2		c.909+163T>C		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.1002+163T>C		intron	N/A	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.1002+163T>C		intron	N/A	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.909+163T>C		intron	N/A	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80405 AN: 151950 Hom.: 22909 Cov.: 33

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.495

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

GnomAD4 genome AF: 0.530 AC: 80527 AN: 152070 Hom.: 22965 Cov.: 33 AF XY: 0.531 AC XY: 39451 AN XY: 74306

African (AFR) AF: 0.757 AC: 31418 AN: 41514

American (AMR) AF: 0.491 AC: 7502 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1402 AN: 3462

East Asian (EAS) AF: 0.525 AC: 2688 AN: 5124

South Asian (SAS) AF: 0.503 AC: 2426 AN: 4824

European-Finnish (FIN) AF: 0.460 AC: 4864 AN: 10574

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28665 AN: 67958

Other (OTH) AF: 0.495 AC: 1048 AN: 2116

Alfa AF: 0.461 Hom.: 19259

Bravo AF: 0.542

Asia WGS AF: 0.550 AC: 1913 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Myopathy, centronuclear, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		-0.042
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: rs2276582; hg19: chr2-127816424; COSMIC: COSV52119095; COSMIC: COSV52119095;