2-127059160-G-C

Variant names:

• chr2-127059160-G-C
• rs75328896
• NM_139343.3:c.858-5C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000316724.10(BIN1):​c.858-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,418,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BIN1 ENST00000316724.10 splice_region, intron
• Scores: Splicing: ADA: 0.001001
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.785
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000316724.10. 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.858-5C>G		splice_region intron	N/A	NP_647593.1
	BIN1	NM_001320642.1		c.777-5C>G		splice_region intron	N/A	NP_001307571.1
	BIN1	NM_001320641.2		c.765-5C>G		splice_region 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.858-5C>G		splice_region intron	N/A	ENSP00000316779.5
	BIN1	ENST00000357970.7	TSL:1	c.858-5C>G		splice_region intron	N/A	ENSP00000350654.3
	BIN1	ENST00000346226.7	TSL:1	c.765-5C>G		splice_region intron	N/A	ENSP00000315411.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 177342 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1418784 Hom.: 0 Cov.: 35 AF XY: 0.00000285 AC XY: 2 AN XY: 701648

African (AFR) AF: 0.00 AC: 0 AN: 32676

American (AMR) AF: 0.00 AC: 0 AN: 38090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 37692

South Asian (SAS) AF: 0.00 AC: 0 AN: 80714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090492

Other (OTH) AF: 0.00 AC: 0 AN: 58824

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.38
DANN	Benign	0.59
PhyloP100		-0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.10
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: rs75328896; hg19: chr2-127816736;