rs2231248

Variant names:

• chr2-74530486-C-G
• rs2231248
• NM_013247.5:c.480C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013247.5(HTRA2):​c.480C>G​(p.Ala160Ala) 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:6
• Conservation: PhyloP100: -1.48
• Publications: 2 publications found

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]

HTRA2 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013247.5. 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
	HTRA2	NM_013247.5	MANE Select	c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 8	NP_037379.1	O43464-1
	HTRA2	NM_001321727.1		c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 7	NP_001308656.1	O43464-3
	HTRA2	NM_001321728.1		c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 7	NP_001308657.1	A0A8Q3SIX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 8	ENSP00000258080.3	O43464-1
	HTRA2	ENST00000437202.2	TSL:1	c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 7	ENSP00000399166.2	O43464-3
	HTRA2	ENST00000352222.7	TSL:1	c.480C>G	p.Ala160Ala	synonymous	Exon 1 of 6	ENSP00000312893.3	O43464-2

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

GnomAD2 exomes AF: 0.00390 AC: 940 AN: 240928 AF XY: 0.00300

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 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

African (AFR) AF: 0.0566 AC: 1896 AN: 33478

American (AMR) AF: 0.00349 AC: 156 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111974

Other (OTH) AF: 0.00361 AC: 218 AN: 60352

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

African (AFR) AF: 0.0550 AC: 2281 AN: 41502

American (AMR) AF: 0.00981 AC: 150 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68000

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	HTRA2-related disorder (1)
-	-	1	Parkinson disease 13, autosomal dominant, susceptibility to (1)
-	-	1	Parkinson disease 13, autosomal dominant, susceptibility to;C4310650:3-methylglutaconic aciduria type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.0
DANN	Benign	0.84
PhyloP100		-1.5
PromoterAI		-0.024	Neutral
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs2231248; hg19: chr2-74757613;