rs2231249

Variant names:

• chr2-74530014-C-G
• rs2231249
• NM_013247.5:c.8C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-74530014-C-G
• chr2-74530014-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013247.5(HTRA2):​c.8C>G​(p.Ala3Gly) 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. 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. A3V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA2 NM_013247.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.676
• Publications: 0 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38929206).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	NM_013247.5	MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 8	NP_037379.1
	HTRA2	NM_001321727.1		c.8C>G	p.Ala3Gly	missense	Exon 1 of 7	NP_001308656.1
	HTRA2	NM_001321728.1		c.8C>G	p.Ala3Gly	missense	Exon 1 of 7	NP_001308657.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 8	ENSP00000258080.3
	HTRA2	ENST00000437202.2	TSL:1	c.8C>G	p.Ala3Gly	missense	Exon 1 of 7	ENSP00000399166.2
	HTRA2	ENST00000352222.7	TSL:1	c.8C>G	p.Ala3Gly	missense	Exon 1 of 6	ENSP00000312893.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.037	D
MutationAssessor	Benign	0.81	L
PhyloP100		0.68
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.16
MutPred		0.26		Loss of stability (P = 0.0156)
MVP		0.96
MPC		2.0
ClinPred		0.79	D
GERP RS		5.5
PromoterAI		-0.084	Neutral
Varity_R		0.57
gMVP		0.42
Mutation Taster		=90/10	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: rs2231249; hg19: chr2-74757141; COSMIC: COSV106053194; COSMIC: COSV106053194;