rs6751560

Positions:

• chr2-85558951-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.339C>T​(p.Asp113=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0248 in 1,613,668 control chromosomes in the GnomAD database, including 928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (265 hom., cov: 32)
  • Exomes 𝑓: 0.023 (663 hom.)
• Consequence: GGCX NM_000821.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.01

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=-0.44).
• BP6: Variant 2-85558951-G-A is Benign according to our data. Variant chr2-85558951-G-A is described in ClinVar as [Benign]. Clinvar id is 337275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGCX	NM_000821.7	c.339C>T	p.Asp113=	synonymous_variant	3/15	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.339C>T	p.Asp113=	synonymous_variant	3/15	1	NM_000821.7	ENSP00000233838	P1

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 7001 AN: 152100 Hom.: 262 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0307 AC: 7713 AN: 251472 Hom.: 218 AF XY: 0.0285 AC XY: 3873 AN XY: 135914

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0416

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.00511

Gnomad SAS exome AF: 0.0206

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0226 AC: 33066 AN: 1461450 Hom.: 663 Cov.: 32 AF XY: 0.0224 AC XY: 16285 AN XY: 727052

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0408

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00557

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.0477

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0462 AC: 7031 AN: 152218 Hom.: 265 Cov.: 32 AF XY: 0.0453 AC XY: 3374 AN XY: 74424

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0410

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0257 Hom.: 101

Bravo AF: 0.0477

Asia WGS AF: 0.0280 AC: 99 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0187

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 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.44
CADD	Benign	10
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6751560; hg19: chr2-85786074;