rs2239586

Variant names:

• chr10-122489719-C-T
• rs2239586
• NM_002775.5:c.777+93C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-122489719-C-T
• chr10-122489719-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002775.5(HTRA1):​c.777+93C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,198,730 control chromosomes in the GnomAD database, including 15,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1992 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13111 hom.)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.778
• Publications: 10 publications found

Genes affected

HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

HTRA1 Gene-Disease associations (from GenCC):

• CARASIL syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• genetic cerebral small vessel disease

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• HTRA1-related autosomal dominant cerebral small vessel disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-122489719-C-T is Benign according to our data. Variant chr10-122489719-C-T is described in ClinVar as Benign. ClinVar VariationId is 1273644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002775.5. 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
	HTRA1	NM_002775.5	MANE Select	c.777+93C>T		intron	N/A	NP_002766.1	Q92743

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.777+93C>T		intron	N/A	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.777+93C>T		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.777+93C>T		intron	N/A	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22607 AN: 151574 Hom.: 1985 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.0916

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.139 AC: 145415 AN: 1047038 Hom.: 13111 AF XY: 0.147 AC XY: 78026 AN XY: 531594

African (AFR) AF: 0.162 AC: 4052 AN: 25014

American (AMR) AF: 0.147 AC: 5297 AN: 35984

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3099 AN: 23114

East Asian (EAS) AF: 0.353 AC: 12159 AN: 34474

South Asian (SAS) AF: 0.338 AC: 24456 AN: 72416

European-Finnish (FIN) AF: 0.103 AC: 4287 AN: 41494

Middle Eastern (MID) AF: 0.184 AC: 635 AN: 3450

European-Non Finnish (NFE) AF: 0.110 AC: 84249 AN: 764424

Other (OTH) AF: 0.154 AC: 7181 AN: 46668

GnomAD4 genome AF: 0.149 AC: 22651 AN: 151692 Hom.: 1992 Cov.: 32 AF XY: 0.154 AC XY: 11409 AN XY: 74114

African (AFR) AF: 0.162 AC: 6702 AN: 41316

American (AMR) AF: 0.171 AC: 2605 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3468

East Asian (EAS) AF: 0.367 AC: 1894 AN: 5166

South Asian (SAS) AF: 0.343 AC: 1629 AN: 4754

European-Finnish (FIN) AF: 0.0916 AC: 960 AN: 10486

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7746 AN: 67944

Other (OTH) AF: 0.162 AC: 340 AN: 2100

Alfa AF: 0.123 Hom.: 2122

Bravo AF: 0.154

Asia WGS AF: 0.320 AC: 1117 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239586; hg19: chr10-124249235; COSMIC: COSV64564398;