Variant chr8-22623989-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018688.6(BIN3):c.541G>A(p.Glu181Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BIN3
NM_018688.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77

Variant links:

Genes affected

BIN3 (HGNC:1054): (bridging integrator 3) The product of this gene is a member of the BAR domain protein family. The encoded protein is comprised solely of a BAR domain which is predicted to form coiled-coil structures and proposed to mediate dimerization, sense and induce membrane curvature, and bind small GTPases. BAR domain proteins have been implicated in endocytosis, intracellular transport, and a diverse set of other processes. [provided by RefSeq, Jul 2008]

BIN3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BIN3	NM_018688.6 linkuse as main transcript	c.541G>A	p.Glu181Lys	missense_variant	8/9	ENST00000276416.11	NP_061158.1
BIN3	NM_001363046.2 linkuse as main transcript	c.397G>A	p.Glu133Lys	missense_variant	7/8		NP_001349975.1
BIN3	XM_047421995.1 linkuse as main transcript	c.379G>A	p.Glu127Lys	missense_variant	5/6		XP_047277951.1
BIN3	NR_156436.2 linkuse as main transcript	n.611G>A		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIN3	ENST00000276416.11 linkuse as main transcript	c.541G>A	p.Glu181Lys	missense_variant	8/9	1	NM_018688.6	ENSP00000276416	P1	Q9NQY0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460500

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726482

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00152

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.541G>A (p.E181K) alteration is located in exon 8 (coding exon 8) of the BIN3 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the glutamic acid (E) at amino acid position 181 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.0055

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;T

Eigen

Benign

0.029

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

0.93

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.024

D;D;D

Polyphen

0.47

P;.;.

Vest4

0.47

MutPred

0.42

Gain of MoRF binding (P = 0.0026);.;.;

MVP

0.65

ClinPred

0.89

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over