7-139575149-C-A

Variant names:

• chr7-139575149-C-A
• rs56300656
• NM_022740.5:c.3105G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022740.5(HIPK2):​c.3105G>T​(p.Gln1035His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1035Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HIPK2 NM_022740.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29614413).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022740.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIPK2	NM_022740.5	MANE Select	c.3105G>T	p.Gln1035His	missense	Exon 14 of 15	NP_073577.3
	HIPK2	NM_001113239.3		c.3024G>T	p.Gln1008His	missense	Exon 14 of 15	NP_001106710.1	Q9H2X6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIPK2	ENST00000406875.8	TSL:1 MANE Select	c.3105G>T	p.Gln1035His	missense	Exon 14 of 15	ENSP00000385571.3	Q9H2X6-1
	HIPK2	ENST00000428878.6	TSL:1	c.3024G>T	p.Gln1008His	missense	Exon 14 of 15	ENSP00000413724.2	Q9H2X6-3
	HIPK2	ENST00000907407.1		c.3021G>T	p.Gln1007His	missense	Exon 14 of 15	ENSP00000577466.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442306 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715544

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 41802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.00 AC: 0 AN: 38954

South Asian (SAS) AF: 0.00 AC: 0 AN: 82878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103292

Other (OTH) AF: 0.00 AC: 0 AN: 59598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.72	T
PhyloP100		-0.12
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.063	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.45
MutPred		0.14		Loss of solvent accessibility (P = 0.0152)
MVP		0.74
MPC		1.1
ClinPred		0.45	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.55
Mutation Taster		=51/48	polymorphism

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

Other links and lift over

dbSNP: rs56300656; hg19: chr7-139259895;