2-127094445-G-C

Variant names:

• chr2-127094445-G-C
• rs10207628
• NM_139343.3:c.84+12415C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139343.3(BIN1):​c.84+12415C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,064 control chromosomes in the GnomAD database, including 3,879 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3879 hom., cov: 33)
• Consequence: BIN1 NM_139343.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 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.84+12415C>G		intron	N/A	NP_647593.1	O00499-1
	BIN1	NM_001320641.2		c.84+12415C>G		intron	N/A	NP_001307570.1
	BIN1	NM_139344.3		c.84+12415C>G		intron	N/A	NP_647594.1	O00499-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIN1	ENST00000316724.10	TSL:1 MANE Select	c.84+12415C>G		intron	N/A	ENSP00000316779.5	O00499-1
	BIN1	ENST00000357970.7	TSL:1	c.84+12415C>G		intron	N/A	ENSP00000350654.3	O00499-5
	BIN1	ENST00000346226.7	TSL:1	c.84+12415C>G		intron	N/A	ENSP00000315411.3	O00499-2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33089 AN: 151944 Hom.: 3883 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.228

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

GnomAD4 genome AF: 0.218 AC: 33095 AN: 152064 Hom.: 3879 Cov.: 33 AF XY: 0.216 AC XY: 16090 AN XY: 74342

African (AFR) AF: 0.297 AC: 12293 AN: 41456

American (AMR) AF: 0.176 AC: 2696 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 503 AN: 3468

East Asian (EAS) AF: 0.113 AC: 584 AN: 5166

South Asian (SAS) AF: 0.262 AC: 1265 AN: 4830

European-Finnish (FIN) AF: 0.179 AC: 1893 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13153 AN: 67962

Other (OTH) AF: 0.226 AC: 477 AN: 2106

Alfa AF: 0.0890 Hom.: 120

Bravo AF: 0.219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.59
PhyloP100		0.64
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: rs10207628; hg19: chr2-127852021;