rs587783345

Variant names:

• chr2-127062201-C-T
• rs61748157
• NM_139343.3:c.775-4G>A

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.775-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,600,218 control chromosomes in the GnomAD database, including 13,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (962 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12511 hom.)
• Consequence: BIN1 NM_139343.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001907
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.02
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-127062201-C-T is Benign according to our data. Variant chr2-127062201-C-T is described in ClinVar as Benign. ClinVar VariationId is 158019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 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.775-4G>A		splice_region intron	N/A	NP_647593.1	O00499-1
	BIN1	NM_001320642.1		c.694-4G>A		splice_region intron	N/A	NP_001307571.1	O00499
	BIN1	NM_001320641.2		c.682-4G>A		splice_region 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.775-4G>A		splice_region intron	N/A	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.775-4G>A		splice_region intron	N/A	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.682-4G>A		splice_region intron	N/A	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15895 AN: 152118 Hom.: 961 Cov.: 33

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.113 AC: 25576 AN: 226228 AF XY: 0.121

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.0689

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.126 AC: 182663 AN: 1447980 Hom.: 12511 Cov.: 33 AF XY: 0.129 AC XY: 92414 AN XY: 718830

African (AFR) AF: 0.0553 AC: 1842 AN: 33318

American (AMR) AF: 0.0699 AC: 3016 AN: 43146

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2901 AN: 25796

East Asian (EAS) AF: 0.0182 AC: 714 AN: 39334

South Asian (SAS) AF: 0.201 AC: 16901 AN: 84004

European-Finnish (FIN) AF: 0.116 AC: 6008 AN: 51862

Middle Eastern (MID) AF: 0.160 AC: 916 AN: 5742

European-Non Finnish (NFE) AF: 0.129 AC: 143021 AN: 1104898

Other (OTH) AF: 0.123 AC: 7344 AN: 59880

GnomAD4 genome AF: 0.104 AC: 15900 AN: 152238 Hom.: 962 Cov.: 33 AF XY: 0.106 AC XY: 7899 AN XY: 74432

African (AFR) AF: 0.0612 AC: 2543 AN: 41554

American (AMR) AF: 0.100 AC: 1530 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3472

East Asian (EAS) AF: 0.0207 AC: 107 AN: 5174

South Asian (SAS) AF: 0.193 AC: 930 AN: 4820

European-Finnish (FIN) AF: 0.113 AC: 1198 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8680 AN: 68000

Other (OTH) AF: 0.119 AC: 251 AN: 2116

Alfa AF: 0.110 Hom.: 460

Bravo AF: 0.0972

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Myopathy, centronuclear, 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.77
PhyloP100		-1.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0040
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: rs61748157; hg19: chr2-127819777;