7-139626708-C-A

Variant names:

• chr7-139626708-C-A
• NM_022740.5:c.1512G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022740.5(HIPK2):​c.1512G>T​(p.Leu504Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIPK2 NM_022740.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.860

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIPK2	NM_022740.5	c.1512G>T	p.Leu504Phe	missense_variant	Exon 6 of 15	ENST00000406875.8	NP_073577.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIPK2	ENST00000406875.8	c.1512G>T	p.Leu504Phe	missense_variant	Exon 6 of 15	1	NM_022740.5	ENSP00000385571.3
HIPK2	ENST00000428878.6	c.1512G>T	p.Leu504Phe	missense_variant	Exon 6 of 15	1		ENSP00000413724.2
HIPK2	ENST00000342645.7	c.1491G>T	p.Leu497Phe	missense_variant	Exon 5 of 11	5		ENSP00000343108.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1512G>T (p.L504F) alteration is located in exon (coding exon ) of the HIPK2 gene. This alteration results from a G to T substitution at nucleotide position 1512, causing the leucine (L) at amino acid position 504 to be replaced by a phenylalanine (F). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.33	N
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.31	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.79
MutPred		0.74		Gain of methylation at K505 (P = 0.0263);Gain of methylation at K505 (P = 0.0263);.;
MVP		0.94
MPC		1.4
ClinPred		0.97	D
GERP RS		-3.9
Varity_R		0.71
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-139311454;