rs75328896

chr2-127059160-G-Achr2-127059160-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_139343.3(BIN1):c.858-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,571,044 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: BIN1 NM_139343.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003996
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.785

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-127059160-G-A is Benign according to our data. Variant chr2-127059160-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00202 (308/152264) while in subpopulation AFR AF= 0.00722 (300/41532). AF 95% confidence interval is 0.00655. There are 1 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.858-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.858-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000434 AC: 77 AN: 177342 Hom.: 0 AF XY: 0.000379 AC XY: 36 AN XY: 95038

Gnomad AFR exome AF: 0.00698

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.000186 AC: 264 AN: 1418780 Hom.: 1 Cov.: 35 AF XY: 0.000144 AC XY: 101 AN XY: 701648

Gnomad4 AFR exome AF: 0.00689

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.000442

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74468

Gnomad4 AFR AF: 0.00722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2017

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. -

BIN1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Myopathy, centronuclear, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.32
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0020
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: rs75328896; hg19: chr2-127816736;