rs699664

chr2-85553413-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000821.7(GGCX):c.974G>A(p.Arg325Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,492 control chromosomes in the GnomAD database, including 92,245 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13667 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78578 hom.)
• Consequence: GGCX NM_000821.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.181

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.222843E-6).
• BP6: Variant 2-85553413-C-T is Benign according to our data. Variant chr2-85553413-C-T is described in ClinVar as [Benign]. Clinvar id is 337268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.974G>A	p.Arg325Gln	missense_variant	8/15	ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.974G>A	p.Arg325Gln	missense_variant	8/15	1	NM_000821.7	P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60559 AN: 151986 Hom.: 13634 Cov.: 33

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.371

GnomAD3 exomes AF: 0.310 AC: 77677 AN: 250364 Hom.: 13382 AF XY: 0.304 AC XY: 41114 AN XY: 135422

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.319

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.328

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.322 AC: 469900 AN: 1461388 Hom.: 78578 Cov.: 37 AF XY: 0.317 AC XY: 230564 AN XY: 727014

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.399 AC: 60639 AN: 152104 Hom.: 13667 Cov.: 33 AF XY: 0.393 AC XY: 29213 AN XY: 74340

Gnomad4 AFR AF: 0.619

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.374

Alfa AF: 0.334 Hom.: 19737

Bravo AF: 0.407

TwinsUK AF: 0.331 AC: 1229

ALSPAC AF: 0.328 AC: 1263

ESP6500AA AF: 0.601 AC: 2648

ESP6500EA AF: 0.326 AC: 2804

ExAC AF: 0.319 AC: 38690

Asia WGS AF: 0.301 AC: 1050 AN: 3478

EpiCase AF: 0.324

EpiControl AF: 0.324

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	This variant is associated with the following publications: (PMID: 24231026, 21704322, 17029979, 30981116, 33507293) -
Benign, criteria provided, single submitter	clinical testing	Invitae	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

Mar 06, 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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	11
Dann	Benign	0.60
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.10	T;T
MetaRNN	Benign	0.0000062	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.18
Sift	Benign	0.55	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0030	B;.
Vest4		0.024
MPC		0.32
ClinPred		0.0014	T
GERP RS		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs699664; hg19: chr2-85780536; COSMIC: COSV52087245; COSMIC: COSV52087245;