rs10179904

chr2-85552984-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000821.7(GGCX):c.1242C>T(p.Thr414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,666 control chromosomes in the GnomAD database, including 12,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1010 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11544 hom.)
• Consequence: GGCX NM_000821.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.42

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-85552984-G-A is Benign according to our data. Variant chr2-85552984-G-A is described in ClinVar as [Benign]. Clinvar id is 337265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.1242C>T	p.Thr414=	synonymous_variant	9/15	ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.1242C>T	p.Thr414=	synonymous_variant	9/15	1	NM_000821.7	P1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17119 AN: 152174 Hom.: 1009 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0789

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.114 AC: 28726 AN: 251456 Hom.: 1875 AF XY: 0.120 AC XY: 16313 AN XY: 135904

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0584

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.123 AC: 179687 AN: 1461374 Hom.: 11544 Cov.: 33 AF XY: 0.125 AC XY: 91098 AN XY: 727008

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0719

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0613

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.0801

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.112 AC: 17130 AN: 152292 Hom.: 1010 Cov.: 32 AF XY: 0.113 AC XY: 8421 AN XY: 74468

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.0789

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.122

Alfa AF: 0.121 Hom.: 1639

Bravo AF: 0.113

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	-0.40
Cadd	Benign	10
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10179904; hg19: chr2-85780107; COSMIC: COSV52087439; COSMIC: COSV52087439;