5-55161011-C-G

Variant names:

• chr5-55161011-C-G
• NM_001008397.4:c.222C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001008397.4(GPX8):​c.222C>G​(p.Asn74Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPX8 NM_001008397.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

Genes affected

GPX8 (HGNC:33100): (glutathione peroxidase 8 (putative)) Enables peroxidase activity. Predicted to be involved in cellular response to oxidative stress. Predicted to be located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

CDC20B (HGNC:24222): (cell division cycle 20B) Predicted to enable anaphase-promoting complex binding activity and ubiquitin ligase activator activity. Predicted to be involved in anaphase-promoting complex-dependent catabolic process and positive regulation of anaphase-promoting complex-dependent catabolic process. Predicted to be part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX8	NM_001008397.4	c.222C>G	p.Asn74Lys	missense_variant	Exon 2 of 3	ENST00000503787.6	NP_001008398.2
CDC20B	NM_001170402.1	c.126+11577G>C		intron_variant	Intron 2 of 11	ENST00000381375.7	NP_001163873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX8	ENST00000503787.6	c.222C>G	p.Asn74Lys	missense_variant	Exon 2 of 3	1	NM_001008397.4	ENSP00000423822.1
CDC20B	ENST00000381375.7	c.126+11577G>C		intron_variant	Intron 2 of 11	1	NM_001170402.1	ENSP00000370781.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.222C>G (p.N74K) alteration is located in exon 2 (coding exon 2) of the GPX8 gene. This alteration results from a C to G substitution at nucleotide position 222, causing the asparagine (N) at amino acid position 74 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.93		Gain of methylation at N74 (P = 0.0036);.;
MVP		0.65
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr5-54456839;