Genetic Variant HIPK2:p.Ala628Thr (chr7-139614394-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022740.5(HIPK2):c.1882G>A(p.Ala628Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HIPK2
NM_022740.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

HIPK2 (HGNC:14402): (homeodomain interacting protein kinase 2) This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

HIPK2 links:

LOC105375530 (HGNC:):

LOC105375530 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24046275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIPK2	NM_022740.5 link	c.1882G>A	p.Ala628Thr	missense_variant	Exon 8 of 15	ENST00000406875.8	NP_073577.3	Q9H2X6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HIPK2	ENST00000406875.8 link	c.1882G>A	p.Ala628Thr	missense_variant	Exon 8 of 15	1	NM_022740.5	ENSP00000385571.3	Q9H2X6-1
HIPK2	ENST00000428878.6 link	c.1801G>A	p.Ala601Thr	missense_variant	Exon 8 of 15	1		ENSP00000413724.2	Q9H2X6-3
HIPK2	ENST00000342645.7 link	c.1861G>A	p.Ala621Thr	missense_variant	Exon 7 of 11	5		ENSP00000343108.7	H7BXX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1424762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706818

Gnomad4 AFR exome

AF:

0.00

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1882G>A (p.A628T) alteration is located in exon (coding exon ) of the HIPK2 gene. This alteration results from a G to A substitution at nucleotide position 1882, causing the alanine (A) at amino acid position 628 to be replaced by a threonine (T). 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

0.14

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;.;T

Eigen

Benign

-0.034

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

T;D;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.39

N;N;.

REVEL

Benign

0.042

Sift

Benign

0.34

T;T;.

Sift4G

Benign

0.68

T;T;T

Polyphen

0.58

P;B;.

Vest4

0.44

MutPred

0.18

Gain of glycosylation at A628 (P = 0.0105);.;.;

MVP

0.70

MPC

0.44

ClinPred

0.47

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over