6-142753171-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006734.4(HIVEP2):c.7277A>G(p.Lys2426Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HIVEP2 NM_006734.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.919

Genes affected

HIVEP2 (HGNC:4921): (HIVEP zinc finger 2) This gene encodes a member of a family of closely related, large, zinc finger-containing transcription factors. The encoded protein regulates transcription by binding to regulatory regions of various cellular and viral genes that maybe involved in growth, development and metastasis. The protein contains the ZAS domain comprised of two widely separated regions of zinc finger motifs, a stretch of highly acidic amino acids and a serine/threonine-rich sequence. [provided by RefSeq, Nov 2012]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HIVEP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.058794826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP2	NM_006734.4	c.7277A>G	p.Lys2426Arg	missense_variant	10/10	ENST00000367603.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP2	ENST00000367603.8	c.7277A>G	p.Lys2426Arg	missense_variant	10/10	1	NM_006734.4	P1
	ENST00000437067.1	n.96-335T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461618 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2426 of the HIVEP2 protein (p.Lys2426Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HIVEP2-related conditions. This missense change has been observed in at least one individual who was not affected with HIVEP2-related conditions (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.043	D;D;D
Sift4G	Benign	0.43	T;T;T
Polyphen		0.10	B;B;B
Vest4		0.22
MutPred		0.19		Loss of ubiquitination at K2426 (P = 0.002);Loss of ubiquitination at K2426 (P = 0.002);Loss of ubiquitination at K2426 (P = 0.002);
MVP		0.20
MPC		0.61
ClinPred		0.22	T
GERP RS		4.8
Varity_R		0.044
gMVP		0.068

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

Other links and lift over

dbSNP: rs1774963428; hg19: chr6-143074308;