rs6704863

Variant names:

• chr2-85546518-C-T
• rs6704863
• NM_000821.7:c.*3416G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-85546518-C-T
• chr2-85546518-C-A
• chr2-85546518-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.*3416G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 138,016 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (653 hom., cov: 32)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: GGCX NM_000821.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.145
• Publications: 1 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 (BayesDel_noAF=-0.8).
• BP6: Variant 2-85546518-C-T is Benign according to our data. Variant chr2-85546518-C-T is described in ClinVar as Benign. ClinVar VariationId is 337202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 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.*3416G>A		3_prime_UTR	Exon 15 of 15	NP_000812.2
	GGCX	NM_001142269.4		c.*3416G>A		3_prime_UTR	Exon 14 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.*3416G>A		3_prime_UTR	Exon 15 of 15	ENSP00000233838.3	P38435-1
	GGCX	ENST00000911478.1		c.*3416G>A		3_prime_UTR	Exon 15 of 15	ENSP00000581537.1

Frequencies

GnomAD3 genomes AF: 0.0811 AC: 11180 AN: 137846 Hom.: 655 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00233

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0140

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0817

GnomAD4 exome AF: 0.0714 AC: 4 AN: 56 Hom.: 0 Cov.: 0 AF XY: 0.0870 AC XY: 4 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0435 AC: 2 AN: 46

Other (OTH) AF: 0.250 AC: 2 AN: 8

GnomAD4 genome AF: 0.0811 AC: 11188 AN: 137960 Hom.: 653 Cov.: 32 AF XY: 0.0793 AC XY: 5325 AN XY: 67150

African (AFR) AF: 0.198 AC: 6918 AN: 34894

American (AMR) AF: 0.0542 AC: 764 AN: 14104

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 136 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4838

South Asian (SAS) AF: 0.0134 AC: 58 AN: 4340

European-Finnish (FIN) AF: 0.0182 AC: 174 AN: 9540

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.0463 AC: 2956 AN: 63862

Other (OTH) AF: 0.0808 AC: 154 AN: 1906

Alfa AF: 0.0270 Hom.: 14

Bravo AF: 0.0789

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	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	-0.80
CADD	Benign	1.5
DANN	Benign	0.42
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6704863; hg19: chr2-85773641;