chr17-2042216-G-C

Variant names:

• chr17-2042216-G-C
• NM_080822.3:c.169G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080822.3(OVCA2):​c.169G>C​(p.Ala57Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,276,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: OVCA2 NM_080822.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.340

Genes affected

OVCA2 (HGNC:24203): (OVCA2 serine hydrolase domain containing) Involved in response to retinoic acid. Located in cytoplasm. Biomarker of ovarian cancer. [provided by Alliance of Genome Resources, Apr 2022]

DPH1 (HGNC:3003): (diphthamide biosynthesis 1) The protein encoded by this gene is an enzyme involved in the biosynthesis of diphthamide, a modified histidine found only in elongation factor-2 (EEF2). Diphthamide residues in EEF2 are targeted for ADP-ribosylation by diphtheria toxin and Pseudomonas exotoxin A. Defects in this gene have been associated with both ovarian cancer and autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24473119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OVCA2	NM_080822.3	c.169G>C	p.Ala57Pro	missense_variant	Exon 1 of 2	ENST00000572195.3	NP_543012.1
DPH1	NM_001383.6	c.*18+341G>C		intron_variant	Intron 12 of 12	ENST00000263083.12	NP_001374.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OVCA2	ENST00000572195.3	c.169G>C	p.Ala57Pro	missense_variant	Exon 1 of 2	1	NM_080822.3	ENSP00000461388.1
DPH1	ENST00000263083.12	c.*18+341G>C		intron_variant	Intron 12 of 12	1	NM_001383.6	ENSP00000263083.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000313 AC: 4 AN: 1276740 Hom.: 0 Cov.: 36 AF XY: 0.00000483 AC XY: 3 AN XY: 621200

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: 0.00

Gnomad4 FIN exome AF: 0.0000326

Gnomad4 NFE exome AF: 0.00000291

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>C (p.A57P) alteration is located in exon 1 (coding exon 1) of the OVCA2 gene. This alteration results from a G to C substitution at nucleotide position 169, causing the alanine (A) at amino acid position 57 to be replaced by a proline (P). 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	Benign	0.065
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.25	T
Polyphen		0.90	P
Vest4		0.49
MutPred		0.50		Gain of relative solvent accessibility (P = 0.005);
MVP		0.25
MPC		0.030
ClinPred		0.63	D
GERP RS		2.1
Varity_R		0.10
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1945510;