rs78967885

Variant names:

• chr2-127053411-G-A
• rs78967885
• NM_139343.3:c.1263+11C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_139343.3(BIN1):​c.1263+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00909 in 1,613,860 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (9 hom., cov: 34)
  • Exomes 𝑓: 0.0091 (79 hom.)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.429
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-127053411-G-A is Benign according to our data. Variant chr2-127053411-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210527.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00881 (1342/152334) while in subpopulation NFE AF = 0.0121 (822/68022). AF 95% confidence interval is 0.0114. There are 9 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD,SD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	NM_139343.3	MANE Select	c.1263+11C>T		intron	N/A	NP_647593.1
	BIN1	NM_001320642.1		c.1182+11C>T		intron	N/A	NP_001307571.1
	BIN1	NM_001320641.2		c.1170+11C>T		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.1263+11C>T		intron	N/A	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.1134+11C>T		intron	N/A	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.1039-1049C>T		intron	N/A	ENSP00000315411.3

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1343 AN: 152216 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00825 AC: 2065 AN: 250272 AF XY: 0.00785

Gnomad AFR exome AF: 0.00633

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00912 AC: 13334 AN: 1461526 Hom.: 79 Cov.: 31 AF XY: 0.00883 AC XY: 6417 AN XY: 727050

African (AFR) AF: 0.00538 AC: 180 AN: 33472

American (AMR) AF: 0.00217 AC: 97 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26130

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39684

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86190

European-Finnish (FIN) AF: 0.0180 AC: 963 AN: 53368

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0104 AC: 11605 AN: 1111848

Other (OTH) AF: 0.00737 AC: 445 AN: 60378

GnomAD4 genome AF: 0.00881 AC: 1342 AN: 152334 Hom.: 9 Cov.: 34 AF XY: 0.00918 AC XY: 684 AN XY: 74488

African (AFR) AF: 0.00568 AC: 236 AN: 41580

American (AMR) AF: 0.00255 AC: 39 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 822 AN: 68022

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00903 Hom.: 3

Bravo AF: 0.00756

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.97
DANN	Benign	0.47
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78967885; hg19: chr2-127810987;