6-142759813-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_006734.4(HIVEP2):​c.6475G>C​(p.Gly2159Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,460,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

HIVEP2
NM_006734.4 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.63
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant 6-142759813-C-G is Benign according to our data. Variant chr6-142759813-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3106061.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HIVEP2NM_006734.4 linkc.6475G>C p.Gly2159Arg missense_variant Exon 9 of 10 ENST00000367603.8 NP_006725.3 P31629

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HIVEP2ENST00000367603.8 linkc.6475G>C p.Gly2159Arg missense_variant Exon 9 of 10 1 NM_006734.4 ENSP00000356575.2 P31629

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248328
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134726
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:
0.000165
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1460548
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
726632
show subpopulations
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:
0.000186
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 43 Uncertain:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The observed missense c.6475G>C (p.Gly2159Arg) variant in HIVEP2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Another variant on the same codon [c.6475G>T, p.Gly2159X] of HIVEP2 gene has been reported previously in an individual affected with developmental delay, intellectual disabilities, and mild dysmorphic features (Steinfeld et al., 2016). The p.Gly2159Arg variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Computational evidence (Polyphen - Probably Damaging, SIFT - Tolerated and MutationTaster - Disease Causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Gly2159Arg in HIVEP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 2159 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Inborn genetic diseases Benign:1
Feb 28, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
T;T;T
Eigen
Uncertain
0.65
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
.;.;D
M_CAP
Benign
0.0076
T
MetaRNN
Uncertain
0.63
D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;L;L
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.14
Sift
Uncertain
0.026
D;D;D
Sift4G
Uncertain
0.043
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.84
MutPred
0.21
Gain of MoRF binding (P = 0.0551);Gain of MoRF binding (P = 0.0551);Gain of MoRF binding (P = 0.0551);
MVP
0.38
MPC
0.81
ClinPred
0.44
T
GERP RS
5.8
Varity_R
0.080
gMVP
0.62

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.

Other links and lift over

dbSNP: rs761993070; hg19: chr6-143080950; API