rs6751560

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000821.7(GGCX):c.339C>T(p.Asp113Asp) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.01

Publications

9 publications found

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

GGCX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GGCX	NM_000821.7	MANE Select	c.339C>T	p.Asp113Asp	synonymous	Exon 3 of 15	NP_000812.2
GGCX	NM_001142269.4		c.168C>T	p.Asp56Asp	synonymous	Exon 2 of 14	NP_001135741.1
GGCX	NM_001311312.2		c.339C>T	p.Asp113Asp	synonymous	Exon 3 of 3	NP_001298241.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GGCX	ENST00000233838.9	TSL:1 MANE Select	c.339C>T	p.Asp113Asp	synonymous	Exon 3 of 15	ENSP00000233838.3
GGCX	ENST00000423570.5	TSL:1	n.384C>T		non_coding_transcript_exon	Exon 3 of 6
GGCX	ENST00000689276.1		c.339C>T	p.Asp113Asp	synonymous	Exon 3 of 15	ENSP00000510012.1

Frequencies

GnomAD3 genomes

AF:

0.0460

AC:

7001

AN:

152100

Hom.:

262

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0307

AC:

7713

AN:

251472

AF XY:

0.0285

show subpopulations

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 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.:

AF XY:

0.0224

AC XY:

16285

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.111

AC:

3724

AN:

33458

American (AMR)

AF:

0.0408

AC:

1826

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

532

AN:

26136

East Asian (EAS)

AF:

0.00557

AC:

221

AN:

39700

South Asian (SAS)

AF:

0.0217

AC:

1874

AN:

86240

European-Finnish (FIN)

AF:

0.0477

AC:

2548

AN:

53418

Middle Eastern (MID)

AF:

0.0324

AC:

187

AN:

5768

European-Non Finnish (NFE)

AF:

0.0186

AC:

20655

AN:

1111622

Other (OTH)

AF:

0.0248

AC:

1499

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1688

3376

5063

6751

8439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

812

1624

2436

3248

4060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0462

AC:

7031

AN:

152218

Hom.:

265

Cov.:

AF XY:

0.0453

AC XY:

3374

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.101

AC:

4183

AN:

41520

American (AMR)

AF:

0.0370

AC:

567

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3468

East Asian (EAS)

AF:

0.00560

AC:

AN:

5174

South Asian (SAS)

AF:

0.0261

AC:

126

AN:

4820

European-Finnish (FIN)

AF:

0.0410

AC:

435

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0222

AC:

1511

AN:

68008

Other (OTH)

AF:

0.0412

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

320

639

959

1278

1598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0289

Hom.:

167

Bravo

AF:

0.0477

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0187

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Vitamin K-dependent clotting factors, combined deficiency of, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over