chr20-63560222-G-A

Variant summary

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

The NM_001037335.2(HELZ2):​c.7606C>T​(p.Arg2536Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,535,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

HELZ2
NM_001037335.2 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.36
Variant links:
Genes affected
HELZ2 (HGNC:30021): (helicase with zinc finger 2) The protein encoded by this gene is a nuclear transcriptional co-activator for peroxisome proliferator activated receptor alpha. The encoded protein contains a zinc finger and is a helicase that appears to be part of the peroxisome proliferator activated receptor alpha interacting complex. This gene is a member of the DNA2/NAM7 helicase gene family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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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=0.17724544).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HELZ2NM_001037335.2 linkuse as main transcriptc.7606C>T p.Arg2536Trp missense_variant 18/20 ENST00000467148.2 NP_001032412.2
HELZ2NM_033405.3 linkuse as main transcriptc.5899C>T p.Arg1967Trp missense_variant 12/14 NP_208384.3
HELZ2XM_024452006.2 linkuse as main transcriptc.7690C>T p.Arg2564Trp missense_variant 16/18 XP_024307774.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HELZ2ENST00000467148.2 linkuse as main transcriptc.7606C>T p.Arg2536Trp missense_variant 18/201 NM_001037335.2 ENSP00000417401 P1Q9BYK8-1
HELZ2ENST00000427522.6 linkuse as main transcriptc.5899C>T p.Arg1967Trp missense_variant 12/141 ENSP00000393257 Q9BYK8-2
HELZ2ENST00000478861.1 linkuse as main transcriptn.559+367C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000812
AC:
12
AN:
147858
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000673
Gnomad ASJ
AF:
0.000292
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000149
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000148
AC:
25
AN:
169118
Hom.:
0
AF XY:
0.000121
AC XY:
11
AN XY:
90828
show subpopulations
Gnomad AFR exome
AF:
0.0000978
Gnomad AMR exome
AF:
0.000115
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000236
Gnomad SAS exome
AF:
0.000413
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000976
Gnomad OTH exome
AF:
0.000217
GnomAD4 exome
AF:
0.0000894
AC:
124
AN:
1387234
Hom.:
0
Cov.:
38
AF XY:
0.0000948
AC XY:
65
AN XY:
686014
show subpopulations
Gnomad4 AFR exome
AF:
0.0000632
Gnomad4 AMR exome
AF:
0.000110
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000843
Gnomad4 SAS exome
AF:
0.000236
Gnomad4 FIN exome
AF:
0.0000485
Gnomad4 NFE exome
AF:
0.0000837
Gnomad4 OTH exome
AF:
0.0000526
GnomAD4 genome
AF:
0.0000812
AC:
12
AN:
147858
Hom.:
0
Cov.:
32
AF XY:
0.0000555
AC XY:
4
AN XY:
72104
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000673
Gnomad4 ASJ
AF:
0.000292
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000149
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000151
Hom.:
0
Bravo
AF:
0.0000529
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000351
AC:
3
ExAC
AF:
0.0000674
AC:
8
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2023The c.7606C>T (p.R2536W) alteration is located in exon 18 (coding exon 17) of the HELZ2 gene. This alteration results from a C to T substitution at nucleotide position 7606, causing the arginine (R) at amino acid position 2536 to be replaced by a tryptophan (W). 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
0.084
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
.;D
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.080
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Uncertain
0.088
D
MutationAssessor
Uncertain
2.2
.;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.42
Sift
Benign
0.090
T;D
Sift4G
Uncertain
0.044
D;T
Polyphen
1.0
D;D
Vest4
0.29
MVP
0.42
MPC
0.54
ClinPred
0.067
T
GERP RS
-7.5
Varity_R
0.038
gMVP
0.42

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: rs369824932; hg19: chr20-62191575; API