rs2231248

Positions:

• chr2-74530486-C-G
• chr2-74530486-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013247.5(HTRA2):​c.480C>G​(p.Ala160=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,609,758 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (47 hom.)
• Consequence: HTRA2 NM_013247.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.48

Genes affected

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-74530486-C-G is Benign according to our data. Variant chr2-74530486-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 337129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA2	NM_013247.5	c.480C>G	p.Ala160=	synonymous_variant	1/8	ENST00000258080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA2	ENST00000258080.8	c.480C>G	p.Ala160=	synonymous_variant	1/8	1	NM_013247.5	P1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2462 AN: 152056 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00390 AC: 940 AN: 240928 Hom.: 15 AF XY: 0.00300 AC XY: 396 AN XY: 131822

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00164 AC: 2388 AN: 1457584 Hom.: 47 Cov.: 33 AF XY: 0.00145 AC XY: 1049 AN XY: 725236

Gnomad4 AFR exome AF: 0.0566

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.0162 AC: 2471 AN: 152174 Hom.: 63 Cov.: 32 AF XY: 0.0156 AC XY: 1161 AN XY: 74388

Gnomad4 AFR AF: 0.0550

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.000770 Hom.: 1

Bravo AF: 0.0183

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Parkinson disease 13, autosomal dominant, susceptibility to;C4310650:3-methylglutaconic aciduria type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Parkinson disease 13, autosomal dominant, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

HTRA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.0
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2231248; hg19: chr2-74757613;