NM_182701.1:c.242-12G>C

Variant names:

• chr6-28506441-C-G
• rs974334
• NM_182701.1:c.242-12G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182701.1(GPX6):​c.242-12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,510,494 control chromosomes in the GnomAD database, including 41,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (7682 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34041 hom.)
• Consequence: GPX6 NM_182701.1 intron
• Scores: Splicing: ADA: 0.0001758
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342
• Publications: 16 publications found

Genes affected

GPX6 (HGNC:4558): (glutathione peroxidase 6) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. Expression of this gene has been observed in embryos and olfactory epithelium; however, the exact function of this gene is not known. This isozyme is a selenoprotein in humans, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. The orthologs of this gene in mouse and rat (and some other species) contain a cysteine (Cys) residue in place of the Sec residue, and their corresponding mRNAs lack SECIS element. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX6	NM_182701.1	c.242-12G>C		intron_variant	Intron 2 of 4	ENST00000361902.5	NP_874360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX6	ENST00000361902.5	c.242-12G>C		intron_variant	Intron 2 of 4	1	NM_182701.1	ENSP00000354581.1
GPX6	ENST00000474923.1	c.242-12G>C		intron_variant	Intron 2 of 3	1		ENSP00000417364.1
GPX6	ENST00000483058.1	n.461-12G>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43582 AN: 151832 Hom.: 7651 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.264 AC: 65781 AN: 249536 AF XY: 0.258

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.532

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.207 AC: 280739 AN: 1358544 Hom.: 34041 Cov.: 22 AF XY: 0.209 AC XY: 142549 AN XY: 681470

African (AFR) AF: 0.491 AC: 15611 AN: 31792

American (AMR) AF: 0.312 AC: 13914 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5659 AN: 25542

East Asian (EAS) AF: 0.496 AC: 19497 AN: 39270

South Asian (SAS) AF: 0.340 AC: 28656 AN: 84310

European-Finnish (FIN) AF: 0.183 AC: 9751 AN: 53352

Middle Eastern (MID) AF: 0.223 AC: 1248 AN: 5596

European-Non Finnish (NFE) AF: 0.171 AC: 173540 AN: 1017130

Other (OTH) AF: 0.226 AC: 12863 AN: 56938

GnomAD4 genome AF: 0.287 AC: 43664 AN: 151950 Hom.: 7682 Cov.: 32 AF XY: 0.290 AC XY: 21510 AN XY: 74274

African (AFR) AF: 0.478 AC: 19776 AN: 41404

American (AMR) AF: 0.280 AC: 4271 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 705 AN: 3468

East Asian (EAS) AF: 0.510 AC: 2635 AN: 5166

South Asian (SAS) AF: 0.347 AC: 1673 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1877 AN: 10566

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11888 AN: 67948

Other (OTH) AF: 0.269 AC: 567 AN: 2106

Alfa AF: 0.151 Hom.: 408

Bravo AF: 0.305

Asia WGS AF: 0.379 AC: 1316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.9
DANN	Benign	0.71
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0080
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: rs974334; hg19: chr6-28474218; COSMIC: COSV62657152;