rs699664

Positions:

chr2-85553413-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000233838.9(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. 15/20 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
ENST00000233838.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.181

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
GGCX	NM_000821.7 linkuse as main transcript	c.974G>A	p.Arg325Gln	missense_variant	8/15	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9 linkuse as main transcript	c.974G>A	p.Arg325Gln	missense_variant	8/15	1	NM_000821.7	ENSP00000233838	P1	P38435-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60559

AN:

151986

Hom.:

13634

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.317

AC XY:

230564

AN XY:

727014

show subpopulations

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.:

AF XY:

0.393

AC XY:

29213

AN XY:

74340

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	- -
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) -

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.10

T;T

MetaRNN

Benign

0.0000062

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.14

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.27

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over