rs2592551

Positions:

• chr2-85553008-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000821.7(GGCX):​c.1218C>T​(p.Arg406=) variant causes a synonymous change. The variant allele was found at a frequency of 0.276 in 1,613,452 control chromosomes in the GnomAD database, including 62,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6889 hom., cov: 32)
  • Exomes 𝑓: 0.27 (56071 hom.)
• Consequence: GGCX NM_000821.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.58

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-85553008-G-A is Benign according to our data. Variant chr2-85553008-G-A is described in ClinVar as [Benign]. Clinvar id is 337266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGCX	NM_000821.7	c.1218C>T	p.Arg406=	synonymous_variant	9/15	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.1218C>T	p.Arg406=	synonymous_variant	9/15	1	NM_000821.7	ENSP00000233838	P1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44973 AN: 151912 Hom.: 6877 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.275

GnomAD3 exomes AF: 0.262 AC: 65780 AN: 251446 Hom.: 9094 AF XY: 0.259 AC XY: 35257 AN XY: 135900

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.319

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.274 AC: 400715 AN: 1461422 Hom.: 56071 Cov.: 35 AF XY: 0.271 AC XY: 197245 AN XY: 727034

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.296 AC: 45010 AN: 152030 Hom.: 6889 Cov.: 32 AF XY: 0.294 AC XY: 21847 AN XY: 74314

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.280

Alfa AF: 0.280 Hom.: 2939

Bravo AF: 0.295

Asia WGS AF: 0.278 AC: 967 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.273

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Vitamin K-dependent clotting factors, combined deficiency of, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.1
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2592551; hg19: chr2-85780131; COSMIC: COSV52087501; COSMIC: COSV52087501;