rs78967885

Positions:

• chr2-127053411-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000316724.10(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 ENST00000316724.10 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.429

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 210527.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}. Variant chr2-127053411-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIN1	NM_139343.3	c.1263+11C>T		intron_variant		ENST00000316724.10	NP_647593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIN1	ENST00000316724.10	c.1263+11C>T		intron_variant		1	NM_139343.3	ENSP00000316779

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

GnomAD3 exomes AF: 0.00825 AC: 2065 AN: 250272 Hom.: 18 AF XY: 0.00785 AC XY: 1063 AN XY: 135422

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 SAS exome AF: 0.0000655

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

Gnomad4 AFR exome AF: 0.00538

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00737

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

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0105 Hom.: 2

Bravo AF: 0.00756

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Myopathy, centronuclear, 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.97
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs78967885; hg19: chr2-127810987;