rs699664

Variant names:

• chr2-85553413-C-T
• rs699664
• NM_000821.7:c.974G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-85553413-C-T
• chr2-85553413-C-A
• chr2-85553413-C-G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:4
• Conservation: PhyloP100: -0.181
• Publications: 101 publications found

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 Gene-Disease associations (from GenCC):

• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000821.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCX	NM_000821.7	MANE Select	c.974G>A	p.Arg325Gln	missense	Exon 8 of 15	NP_000812.2
	GGCX	NM_001142269.4		c.803G>A	p.Arg268Gln	missense	Exon 7 of 14	NP_001135741.1	P38435-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCX	ENST00000233838.9	TSL:1 MANE Select	c.974G>A	p.Arg325Gln	missense	Exon 8 of 15	ENSP00000233838.3	P38435-1
	GGCX	ENST00000911478.1		c.974G>A	p.Arg325Gln	missense	Exon 8 of 15	ENSP00000581537.1
	GGCX	ENST00000896458.1		c.974G>A	p.Arg325Gln	missense	Exon 8 of 15	ENSP00000566517.1

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

GnomAD2 exomes AF: 0.310 AC: 77677 AN: 250364 AF XY: 0.304

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 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

African (AFR) AF: 0.630 AC: 21072 AN: 33472

American (AMR) AF: 0.235 AC: 10525 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7033 AN: 26130

East Asian (EAS) AF: 0.313 AC: 12412 AN: 39696

South Asian (SAS) AF: 0.183 AC: 15809 AN: 86258

European-Finnish (FIN) AF: 0.322 AC: 17163 AN: 53362

Middle Eastern (MID) AF: 0.284 AC: 1639 AN: 5768

European-Non Finnish (NFE) AF: 0.328 AC: 364388 AN: 1111604

Other (OTH) AF: 0.329 AC: 19859 AN: 60374

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

African (AFR) AF: 0.619 AC: 25705 AN: 41518

American (AMR) AF: 0.285 AC: 4357 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 896 AN: 3466

East Asian (EAS) AF: 0.325 AC: 1680 AN: 5166

South Asian (SAS) AF: 0.180 AC: 870 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3571 AN: 10570

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22353 AN: 67980

Other (OTH) AF: 0.374 AC: 789 AN: 2108

Alfa AF: 0.346 Hom.: 42347

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000062	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.18
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.18
Sift	Benign	0.55	T
Sift4G	Benign	0.62	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs699664; hg19: chr2-85780536; COSMIC: COSV52087245; COSMIC: COSV52087245;