Variant 20-63560222-G-A details in Genebe, Genetics Data Aggregator

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

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]

HELZ2 links:

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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
HELZ2	NM_001037335.2 linkuse as main transcript	c.7606C>T	p.Arg2536Trp	missense_variant	18/20	ENST00000467148.2	NP_001032412.2
HELZ2	NM_033405.3 linkuse as main transcript	c.5899C>T	p.Arg1967Trp	missense_variant	12/14		NP_208384.3
HELZ2	XM_024452006.2 linkuse as main transcript	c.7690C>T	p.Arg2564Trp	missense_variant	16/18		XP_024307774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELZ2	ENST00000467148.2 linkuse as main transcript	c.7606C>T	p.Arg2536Trp	missense_variant	18/20	1	NM_001037335.2	ENSP00000417401	P1	Q9BYK8-1
HELZ2	ENST00000427522.6 linkuse as main transcript	c.5899C>T	p.Arg1967Trp	missense_variant	12/14	1		ENSP00000393257		Q9BYK8-2
HELZ2	ENST00000478861.1 linkuse as main transcript	n.559+367C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000812

AC:

AN:

147858

Hom.:

Cov.:

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:

AN:

169118

Hom.:

AF XY:

0.000121

AC XY:

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.:

Cov.:

AF XY:

0.0000948

AC XY:

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:

AN:

147858

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

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.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000351

AC:

ExAC

AF:

0.0000674

AC:

Asia WGS

AF:

0.000866

AC:

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 submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The 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

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

.;D

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.080

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

0.088

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over