rs6720741

Variant names:

• chr2-127059167-G-T
• rs6720741
• NM_139343.3:c.858-12C>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.858-12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,564,704 control chromosomes in the GnomAD database, including 29,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3166 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26706 hom.)
• Consequence: BIN1 NM_139343.3 intron
• Scores: Splicing: ADA: 0.001381
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0720
• 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):

• 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=-0.81).
• BP6: Variant 2-127059167-G-T is Benign according to our data. Variant chr2-127059167-G-T is described in ClinVar as Benign. ClinVar VariationId is 158020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 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.858-12C>A		intron	N/A	NP_647593.1
	BIN1	NM_001320642.1		c.777-12C>A		intron	N/A	NP_001307571.1
	BIN1	NM_001320641.2		c.765-12C>A		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.858-12C>A		intron	N/A	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.858-12C>A		intron	N/A	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.765-12C>A		intron	N/A	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30211 AN: 151654 Hom.: 3162 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.176 AC: 30060 AN: 170668 AF XY: 0.179

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.135

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.193 AC: 272036 AN: 1412932 Hom.: 26706 Cov.: 42 AF XY: 0.191 AC XY: 133556 AN XY: 698274

African (AFR) AF: 0.250 AC: 8115 AN: 32456

American (AMR) AF: 0.108 AC: 4043 AN: 37466

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3861 AN: 25274

East Asian (EAS) AF: 0.106 AC: 3963 AN: 37332

South Asian (SAS) AF: 0.191 AC: 15314 AN: 80306

European-Finnish (FIN) AF: 0.215 AC: 10439 AN: 48504

Middle Eastern (MID) AF: 0.160 AC: 917 AN: 5716

European-Non Finnish (NFE) AF: 0.197 AC: 214642 AN: 1087268

Other (OTH) AF: 0.183 AC: 10742 AN: 58610

GnomAD4 genome AF: 0.199 AC: 30236 AN: 151772 Hom.: 3166 Cov.: 31 AF XY: 0.198 AC XY: 14707 AN XY: 74164

African (AFR) AF: 0.247 AC: 10196 AN: 41322

American (AMR) AF: 0.121 AC: 1851 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.125 AC: 644 AN: 5140

South Asian (SAS) AF: 0.189 AC: 908 AN: 4798

European-Finnish (FIN) AF: 0.219 AC: 2313 AN: 10568

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.196 AC: 13281 AN: 67898

Other (OTH) AF: 0.160 AC: 337 AN: 2102

Alfa AF: 0.188 Hom.: 584

Bravo AF: 0.192

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Myopathy, centronuclear, 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.71
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.098
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: rs6720741; hg19: chr2-127816743;