rs762684

Variant names:

• chr2-85554900-G-A
• rs762684
• ENST00000423570.5:n.1283C>T

Variant summary

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

The ENST00000423570.5(GGCX):​n.1283C>T variant causes a non coding transcript exon 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 ENST00000423570.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.295
• Publications: 8 publications found

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]

GGCX Gene-Disease associations (from GenCC):

• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.725+584C>T		intron_variant	Intron 6 of 14	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.725+584C>T		intron_variant	Intron 6 of 14	1	NM_000821.7	ENSP00000233838.3

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

African (AFR) AF: 0.302 AC: 113 AN: 374

American (AMR) AF: 0.217 AC: 690 AN: 3186

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 51 AN: 254

East Asian (EAS) AF: 0.284 AC: 466 AN: 1642

South Asian (SAS) AF: 0.155 AC: 452 AN: 2920

European-Finnish (FIN) AF: 0.224 AC: 96 AN: 428

Middle Eastern (MID) AF: 0.261 AC: 12 AN: 46

European-Non Finnish (NFE) AF: 0.245 AC: 2675 AN: 10900

Other (OTH) AF: 0.235 AC: 208 AN: 886

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

African (AFR) AF: 0.360 AC: 14925 AN: 41448

American (AMR) AF: 0.224 AC: 3427 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1687 AN: 5180

South Asian (SAS) AF: 0.168 AC: 810 AN: 4818

European-Finnish (FIN) AF: 0.320 AC: 3379 AN: 10568

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19059 AN: 67992

Other (OTH) AF: 0.280 AC: 591 AN: 2108

Alfa AF: 0.280 Hom.: 2588

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
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs762684; hg19: chr2-85782023;