20-63560176-C-T

Variant names:

• chr20-63560176-C-T
• NM_001037335.2:c.7652G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001037335.2(HELZ2):​c.7652G>A​(p.Ser2551Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000788 in 1,269,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: HELZ2 NM_001037335.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELZ2	NM_001037335.2	c.7652G>A	p.Ser2551Asn	missense_variant	Exon 18 of 20	ENST00000467148.2	NP_001032412.2
HELZ2	NM_033405.3	c.5945G>A	p.Ser1982Asn	missense_variant	Exon 12 of 14		NP_208384.3
HELZ2	XM_024452006.2	c.7736G>A	p.Ser2579Asn	missense_variant	Exon 16 of 18		XP_024307774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELZ2	ENST00000467148.2	c.7652G>A	p.Ser2551Asn	missense_variant	Exon 18 of 20	1	NM_001037335.2	ENSP00000417401.1
HELZ2	ENST00000427522.6	c.5945G>A	p.Ser1982Asn	missense_variant	Exon 12 of 14	1		ENSP00000393257.2
HELZ2	ENST00000478861.1	n.559+413G>A		intron_variant	Intron 5 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.88e-7 AC: 1 AN: 1269160 Hom.: 0 Cov.: 42 AF XY: 0.00000159 AC XY: 1 AN XY: 627190

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7652G>A (p.S2551N) alteration is located in exon 18 (coding exon 17) of the HELZ2 gene. This alteration results from a G to A substitution at nucleotide position 7652, causing the serine (S) at amino acid position 2551 to be replaced by an asparagine (N). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.5	.;H
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.51		.;Gain of methylation at K2550 (P = 0.0694);
MVP		0.73
MPC		0.69
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.74
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62191529;