2-127048046-ATTT-ATT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_139343.3(BIN1):​c.*479delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 188,788 control chromosomes in the GnomAD database, including 116 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (111 hom., cov: 33)
  • Exomes 𝑓: 0.019 (5 hom.)
• Consequence: BIN1 NM_139343.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BIN1	NM_139343.3	c.*479delA		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.*479delA		3_prime_UTR_variant	Exon 19 of 19	1	NM_139343.3	ENSP00000316779.5

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4052 AN: 150064 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.000492

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00208

Gnomad OTH AF: 0.0223

GnomAD4 exome AF: 0.0193 AC: 744 AN: 38624 Hom.: 5 Cov.: 0 AF XY: 0.0187 AC XY: 373 AN XY: 19954

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

African (AFR) AF: 0.0481 AC: 35 AN: 728

American (AMR) AF: 0.0729 AC: 217 AN: 2978

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 9 AN: 710

East Asian (EAS) AF: 0.0275 AC: 59 AN: 2142

South Asian (SAS) AF: 0.0216 AC: 117 AN: 5406

European-Finnish (FIN) AF: 0.0110 AC: 23 AN: 2100

Middle Eastern (MID) AF: 0.0200 AC: 2 AN: 100

European-Non Finnish (NFE) AF: 0.0110 AC: 247 AN: 22516

Other (OTH) AF: 0.0180 AC: 35 AN: 1944

⚠️ 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: 0.0272 AC: 4079 AN: 150164 Hom.: 111 Cov.: 33 AF XY: 0.0271 AC XY: 1984 AN XY: 73228

African (AFR) AF: 0.0675 AC: 2772 AN: 41058

American (AMR) AF: 0.0594 AC: 897 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3440

East Asian (EAS) AF: 0.0194 AC: 99 AN: 5106

South Asian (SAS) AF: 0.0235 AC: 111 AN: 4718

European-Finnish (FIN) AF: 0.000492 AC: 5 AN: 10154

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00208 AC: 140 AN: 67318

Other (OTH) AF: 0.0226 AC: 47 AN: 2082

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.0333

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Myopathy, centronuclear, 2 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.10
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: rs367627116; hg19: chr2-127805622; COSMIC: COSV52123279; COSMIC: COSV52123279;