rs2028898

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000821.7(GGCX):c.2085-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,593,924 control chromosomes in the GnomAD database, including 62,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6899 hom., cov: 31)

Exomes 𝑓: 0.27 ( 55582 hom. )

Consequence

GGCX
NM_000821.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.525

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-85550147-G-A is Benign according to our data. Variant chr2-85550147-G-A is described in ClinVar as Benign. ClinVar VariationId is 1278677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7 link	c.2085-21C>T		intron_variant	Intron 14 of 14	ENST00000233838.9	NP_000812.2	P38435-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9 link	c.2085-21C>T		intron_variant	Intron 14 of 14	1	NM_000821.7	ENSP00000233838.3		P38435-1

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44990

AN:

151826

Hom.:

6887

Cov.:

show subpopulations

Gnomad AFR

AF:

0.361

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.278

GnomAD2 exomes

AF:

0.262

AC:

64716

AN:

247468

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.232

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.309

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.275

AC:

396002

AN:

1441980

Hom.:

55582

Cov.:

AF XY:

0.272

AC XY:

195212

AN XY:

718566

show subpopulations

African (AFR)

AF:

0.356

AC:

11777

AN:

33124

American (AMR)

AF:

0.196

AC:

8751

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

6158

AN:

26042

East Asian (EAS)

AF:

0.312

AC:

12373

AN:

39594

South Asian (SAS)

AF:

0.168

AC:

14439

AN:

85810

European-Finnish (FIN)

AF:

0.301

AC:

16029

AN:

53330

Middle Eastern (MID)

AF:

0.214

AC:

1209

AN:

5658

European-Non Finnish (NFE)

AF:

0.282

AC:

308943

AN:

1094124

Other (OTH)

AF:

0.274

AC:

16323

AN:

59642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

13772

27545

41317

55090

68862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10260

20520

30780

41040

51300

<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:

0.296

AC:

45027

AN:

151944

Hom.:

6899

Cov.:

AF XY:

0.294

AC XY:

21860

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.360

AC:

14916

AN:

41412

American (AMR)

AF:

0.224

AC:

3424

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

757

AN:

3470

East Asian (EAS)

AF:

0.326

AC:

1680

AN:

5158

South Asian (SAS)

AF:

0.168

AC:

811

AN:

4818

European-Finnish (FIN)

AF:

0.321

AC:

3384

AN:

10538

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19071

AN:

67958

Other (OTH)

AF:

0.283

AC:

595

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1629

3258

4887

6516

8145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.281

Hom.:

7959

Bravo

AF:

0.296

Asia WGS

AF:

0.278

AC:

966

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.0

(source)

DANN

Benign

0.73

PhyloP100

-0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over