NM_000821.7:c.2084+45G>C

Variant names:

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.2084+45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,425,082 control chromosomes in the GnomAD database, including 5,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 393 hom., cov: 32)

Exomes 𝑓: 0.086 ( 5361 hom. )

Consequence

GGCX
NM_000821.7 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.840

Publications

41 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: 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

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 2-85550510-C-G is Benign according to our data. Variant chr2-85550510-C-G is described in ClinVar as Benign. ClinVar VariationId is 375657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0961 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.2084+45G>C		intron	N/A	NP_000812.2
	GGCX	NM_001142269.4		c.1913+45G>C		intron	N/A	NP_001135741.1	P38435-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GGCX	ENST00000233838.9	TSL:1 MANE Select	c.2084+45G>C	intron	N/A	ENSP00000233838.3	P38435-1
GGCX	ENST00000911478.1		c.2114+45G>C	intron	N/A	ENSP00000581537.1
GGCX	ENST00000896458.1		c.2078+45G>C	intron	N/A	ENSP00000566517.1

Frequencies

GnomAD3 genomes

AF:

0.0587

AC:

8924

AN:

152136

Hom.:

393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.0585

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0981

Gnomad OTH

AF:

0.0473

GnomAD2 exomes

AF:

0.0573

AC:

14316

AN:

249774

AF XY:

0.0572

show subpopulations

Gnomad AFR exome

AF:

0.0150

Gnomad AMR exome

AF:

0.0280

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0606

Gnomad NFE exome

AF:

0.0930

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0858

AC:

109174

AN:

1272828

Hom.:

5361

Cov.:

AF XY:

0.0831

AC XY:

53374

AN XY:

642450

show subpopulations

African (AFR)

AF:

0.0143

AC:

428

AN:

29934

American (AMR)

AF:

0.0290

AC:

1288

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.0419

AC:

1047

AN:

24988

East Asian (EAS)

AF:

0.0000772

AC:

AN:

38846

South Asian (SAS)

AF:

0.0201

AC:

1655

AN:

82418

European-Finnish (FIN)

AF:

0.0614

AC:

3273

AN:

53342

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

5358

European-Non Finnish (NFE)

AF:

0.104

AC:

97658

AN:

939314

Other (OTH)

AF:

0.0694

AC:

3758

AN:

54170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

5350

10699

16049

21398

26748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3270

6540

9810

13080

16350

<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:

0.0586

AC:

8923

AN:

152254

Hom.:

393

Cov.:

AF XY:

0.0541

AC XY:

4030

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0178

AC:

738

AN:

41552

American (AMR)

AF:

0.0351

AC:

536

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0585

AC:

620

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0980

AC:

6668

AN:

68012

Other (OTH)

AF:

0.0468

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

414

827

1241

1654

2068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0721

Hom.:

Bravo

AF:

0.0547

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

GGCX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.2

(source)

DANN

Benign

0.66

PhyloP100

-0.84

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over