Genetic Variant HELZ2:p.Pro2648Ser (chr20-63559254-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001037335.2(HELZ2):c.7942C>T(p.Pro2648Ser) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2648A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HELZ2
NM_001037335.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.712

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032930166).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037335.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELZ2	NM_001037335.2	MANE Select	c.7942C>T	p.Pro2648Ser	missense	Exon 20 of 20	NP_001032412.2	Q9BYK8
	HELZ2	NM_033405.3		c.6235C>T	p.Pro2079Ser	missense	Exon 14 of 14	NP_208384.3	Q9BYK8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HELZ2	ENST00000467148.2	TSL:1 MANE Select	c.7942C>T	p.Pro2648Ser	missense	Exon 20 of 20	ENSP00000417401.1	A0AAA9XBX5
HELZ2	ENST00000850915.1		c.8683C>T	p.Pro2895Ser	missense	Exon 20 of 20	ENSP00000520998.1
HELZ2	ENST00000427522.7		n.6659C>T		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000527

AC:

AN:

189928

AF XY:

0.00000980

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.08e-7

AC:

AN:

1412908

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32930

American (AMR)

AF:

0.00

AC:

AN:

37616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25094

East Asian (EAS)

AF:

0.00

AC:

AN:

38224

South Asian (SAS)

AF:

0.00

AC:

AN:

80860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5058

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1085116

Other (OTH)

AF:

0.00

AC:

AN:

58368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.18

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.58

M_CAP

Benign

0.012

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.77

PhyloP100

-0.71

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.070

REVEL

Benign

0.13

Sift

Benign

0.83

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.025

MutPred

0.28

Gain of MoRF binding (P = 0.0116)

MVP

0.13

MPC

0.18

ClinPred

0.039

GERP RS

-2.2

Varity_R

0.021

gMVP

0.12

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over