Variant chr6-82194488-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015525.4(IBTK):c.3329G>A(p.Gly1110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

IBTK
NM_015525.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.724

Variant links:

Genes affected

IBTK (HGNC:17853): (inhibitor of Bruton tyrosine kinase) Bruton tyrosine kinase (BTK) is a protein tyrosine kinase that is expressed in B cells, macrophages, and neutrophils. The protein encoded by this gene binds to BTK and downregulates BTK's kinase activity. In addition, the encoded protein disrupts BTK-mediated calcium mobilization and negatively regulates the activation of nuclear factor-kappa-B-driven transcription. This gene has a pseudogene on chromosome 18. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

IBTK links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058138847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IBTK	NM_015525.4 linkuse as main transcript	c.3329G>A	p.Gly1110Asp	missense_variant	23/29	ENST00000306270.12
IBTK	NM_001300906.2 linkuse as main transcript	c.3284G>A	p.Gly1095Asp	missense_variant	23/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IBTK	ENST00000306270.12 linkuse as main transcript	c.3329G>A	p.Gly1110Asp	missense_variant	23/29	1	NM_015525.4	P1	Q9P2D0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000440

AC:

AN:

227376

Hom.:

AF XY:

0.00000814

AC XY:

AN XY:

122904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000940

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Jul 06, 2021

The c.3329G>A (p.G1110D) alteration is located in exon 23 (coding exon 22) of the IBTK gene. This alteration results from a G to A substitution at nucleotide position 3329, causing the glycine (G) at amino acid position 1110 to be replaced by an aspartic acid (D). 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

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.20

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.087

M_CAP

Benign

0.012

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.94

N;.;N;N

REVEL

Benign

0.027

Sift

Benign

0.092

T;.;T;T

Sift4G

Benign

0.37

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.15

MutPred

0.16

Gain of disorder (P = 0.171);.;.;.;

MVP

0.27

MPC

0.21

ClinPred

0.067

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.065

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