rs762684

Positions:

• chr2-85554900-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000821.7(GGCX):​c.725+584C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 172,704 control chromosomes in the GnomAD database, including 7,502 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 0.30 (6899 hom., cov: 33)
  • Exomes 𝑓: 0.23 (603 hom.)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.295

Genes affected

GGCX (HGNC:4247): (gamma-glutamyl carboxylase) This gene encodes an integral membrane protein of the rough endoplasmic reticulum that carboxylates glutamate residues of vitamin K-dependent proteins to gamma carboxyl glutamate, a modification that is required for their activity. The vitamin K-dependent protein substrates have a propeptide that binds the enzyme, with carbon dioxide, dioxide, and reduced vitamin K acting as co-substrates. Vitamin K-dependent proteins affect a number of physiologic processes including blood coagulation, prevention of vascular calcification, and inflammation. Allelic variants of this gene have been associated with pseudoxanthoma elasticum-like disorder with associated multiple coagulation factor deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.725+584C>T		intron_variant		ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.725+584C>T		intron_variant		1	NM_000821.7	P1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44987 AN: 151950 Hom.: 6887 Cov.: 33

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.231 AC: 4763 AN: 20636 Hom.: 603 Cov.: 0 AF XY: 0.229 AC XY: 2489 AN XY: 10866

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.296 AC: 45024 AN: 152068 Hom.: 6899 Cov.: 33 AF XY: 0.294 AC XY: 21852 AN XY: 74328

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.280

Alfa AF: 0.277 Hom.: 1354

Bravo AF: 0.296

Asia WGS AF: 0.278 AC: 966 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.8
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs762684; hg19: chr2-85782023;