chr5-55161011-C-G

Variant names:

• chr5-55161011-C-G
• rs1342210323
• NM_001008397.4:c.222C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008397.4. 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
	GPX8	NM_001008397.4	MANE Select	c.222C>G	p.Asn74Lys	missense	Exon 2 of 3	NP_001008398.2	Q8TED1
	CDC20B	NM_001170402.1	MANE Select	c.126+11577G>C		intron	N/A	NP_001163873.1	Q86Y33-1
	GPX8	NM_001306197.2		c.69C>G	p.Asn23Lys	missense	Exon 2 of 3	NP_001293126.1	E7ETY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX8	ENST00000503787.6	TSL:1 MANE Select	c.222C>G	p.Asn74Lys	missense	Exon 2 of 3	ENSP00000423822.1	Q8TED1
	CDC20B	ENST00000381375.7	TSL:1 MANE Select	c.126+11577G>C		intron	N/A	ENSP00000370781.2	Q86Y33-1
	CDC20B	ENST00000296733.5	TSL:1	c.126+11577G>C		intron	N/A	ENSP00000296733.1	Q86Y33-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	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
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs1342210323; hg19: chr5-54456839;