rs138047593

chr2-127050470-T-C

Variant summary

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

The NM_139343.3(BIN1):c.1625A>G(p.Lys542Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,222 control chromosomes in the GnomAD database, including 136 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 0.0079 (3 hom., cov: 34)
  • Exomes 𝑓: 0.011 (133 hom.)
• Consequence: BIN1 NM_139343.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.03

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 (MetaRNN=0.0087840855).
• BP6: Variant 2-127050470-T-C is Benign according to our data. Variant chr2-127050470-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158011.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00794 (1210/152346) while in subpopulation NFE AF= 0.0131 (893/68022). AF 95% confidence interval is 0.0124. There are 3 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIN1	NM_139343.3	c.1625A>G	p.Lys542Arg	missense_variant	18/19	ENST00000316724.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIN1	ENST00000316724.10	c.1625A>G	p.Lys542Arg	missense_variant	18/19	1	NM_139343.3

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1209 AN: 152228 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00925 AC: 2325 AN: 251424 Hom.: 26 AF XY: 0.00909 AC XY: 1236 AN XY: 135906

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0109 AC: 15980 AN: 1461876 Hom.: 133 Cov.: 33 AF XY: 0.0106 AC XY: 7683 AN XY: 727242

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.00897

GnomAD4 genome AF: 0.00794 AC: 1210 AN: 152346 Hom.: 3 Cov.: 34 AF XY: 0.00777 AC XY: 579 AN XY: 74508

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0109 Hom.: 7

Bravo AF: 0.00710

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.0112 AC: 1360

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Myopathy, centronuclear, 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

BIN1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0088	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.082	T;D;T;T;D;T;T;D;T;D;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;P;B;D;B;P;B;B;D;B;D
Vest4		0.18
MPC		0.69
ClinPred		0.021	T
GERP RS		4.6
Varity_R		0.41
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138047593; hg19: chr2-127808046; COSMIC: COSV99035049;