rs11554586

chr2-127106970-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139343.3(BIN1):c.-27C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,600,126 control chromosomes in the GnomAD database, including 22,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1690 hom., cov: 34)
  • Exomes 𝑓: 0.17 (21161 hom.)
• Consequence: BIN1 NM_139343.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-127106970-G-A is Benign according to our data. Variant chr2-127106970-G-A is described in ClinVar as [Benign]. Clinvar id is 262469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127106970-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.-27C>T		5_prime_UTR_variant	1/19	ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.-27C>T		5_prime_UTR_variant	1/19	1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19852 AN: 152072 Hom.: 1684 Cov.: 34

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0996

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.152 AC: 34751 AN: 228148 Hom.: 2860 AF XY: 0.152 AC XY: 19019 AN XY: 125058

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.0711

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.166 AC: 240804 AN: 1447940 Hom.: 21161 Cov.: 32 AF XY: 0.164 AC XY: 118321 AN XY: 720098

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.0861

Gnomad4 SAS exome AF: 0.0707

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.131 AC: 19869 AN: 152186 Hom.: 1690 Cov.: 34 AF XY: 0.129 AC XY: 9578 AN XY: 74394

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.0997

Gnomad4 SAS AF: 0.0646

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.139

Alfa AF: 0.167 Hom.: 422

Bravo AF: 0.126

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Myopathy, centronuclear, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	17
Dann	Benign	0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs11554586; hg19: chr2-127864546; COSMIC: COSV52119136;