2-85560218-C-T

Variant names:

• chr2-85560218-C-T
• rs12714145
• NM_000821.7:c.214+597G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000821.7(GGCX):​c.214+597G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,940 control chromosomes in the GnomAD database, including 12,874 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (12874 hom., cov: 31)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 39 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 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.214+597G>A		intron	N/A	NP_000812.2
	GGCX	NM_001142269.4		c.44-1143G>A		intron	N/A	NP_001135741.1	P38435-2
	GGCX	NM_001311312.2		c.214+597G>A		intron	N/A	NP_001298241.1	A0A8I5QJA4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCX	ENST00000233838.9	TSL:1 MANE Select	c.214+597G>A		intron	N/A	ENSP00000233838.3	P38435-1
	GGCX	ENST00000423570.5	TSL:1	n.259+597G>A		intron	N/A
	GGCX	ENST00000911478.1		c.214+597G>A		intron	N/A	ENSP00000581537.1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62043 AN: 151822 Hom.: 12859 Cov.: 31

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.399

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.409 AC: 62091 AN: 151940 Hom.: 12874 Cov.: 31 AF XY: 0.407 AC XY: 30246 AN XY: 74252

African (AFR) AF: 0.467 AC: 19351 AN: 41406

American (AMR) AF: 0.340 AC: 5193 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3472

East Asian (EAS) AF: 0.385 AC: 1996 AN: 5178

South Asian (SAS) AF: 0.353 AC: 1697 AN: 4808

European-Finnish (FIN) AF: 0.401 AC: 4224 AN: 10540

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27099 AN: 67940

Other (OTH) AF: 0.402 AC: 848 AN: 2108

Alfa AF: 0.403 Hom.: 24568

Bravo AF: 0.408

Asia WGS AF: 0.401 AC: 1392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.7
DANN	Benign	0.68
PhyloP100		-0.0040
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: rs12714145; hg19: chr2-85787341;