chr2-127048046-A-AT

Variant names:

• chr2-127048046-A-AT
• rs367627116
• NM_139343.3:c.*479dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_139343.3(BIN1):​c.*479dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 188,732 control chromosomes in the GnomAD database, including 19 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0084 (18 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1 hom.)
• Consequence: BIN1 NM_139343.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1261/150180) while in subpopulation AFR AF = 0.0271 (1111/41064). AF 95% confidence interval is 0.0257. There are 18 homozygotes in GnomAd4. There are 616 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.*479dupA		3_prime_UTR_variant	Exon 19 of 19	ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.*479dupA		3_prime_UTR_variant	Exon 19 of 19	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1252 AN: 150080 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000579

Gnomad OTH AF: 0.00631

GnomAD4 exome AF: 0.0136 AC: 525 AN: 38552 Hom.: 1 Cov.: 0 AF XY: 0.0133 AC XY: 264 AN XY: 19908

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0232 AC: 17 AN: 732

American (AMR) AF: 0.0108 AC: 32 AN: 2970

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 10 AN: 710

East Asian (EAS) AF: 0.0151 AC: 32 AN: 2120

South Asian (SAS) AF: 0.0133 AC: 72 AN: 5404

European-Finnish (FIN) AF: 0.0128 AC: 27 AN: 2102

Middle Eastern (MID) AF: 0.0204 AC: 2 AN: 98

European-Non Finnish (NFE) AF: 0.0137 AC: 308 AN: 22468

Other (OTH) AF: 0.0128 AC: 25 AN: 1948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00840 AC: 1261 AN: 150180 Hom.: 18 Cov.: 33 AF XY: 0.00841 AC XY: 616 AN XY: 73240

African (AFR) AF: 0.0271 AC: 1111 AN: 41064

American (AMR) AF: 0.00484 AC: 73 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3440

East Asian (EAS) AF: 0.00176 AC: 9 AN: 5108

South Asian (SAS) AF: 0.00212 AC: 10 AN: 4720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10156

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000579 AC: 39 AN: 67322

Other (OTH) AF: 0.00624 AC: 13 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism

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: rs367627116; hg19: chr2-127805622; COSMIC: COSV105006203; COSMIC: COSV105006203;