NM_000821.7:c.540-382C>G

Variant names:

• chr2-85556642-G-C
• rs17026452
• NM_000821.7:c.540-382C>G

Variant summary

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

The NM_000821.7(GGCX):​c.540-382C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,108 control chromosomes in the GnomAD database, including 1,199 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 0.10 (1199 hom., cov: 32)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.898
• Publications: 5 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.540-382C>G		intron_variant	Intron 4 of 14	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.540-382C>G		intron_variant	Intron 4 of 14	1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15808 AN: 151990 Hom.: 1191 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0816

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.104 AC: 15851 AN: 152108 Hom.: 1199 Cov.: 32 AF XY: 0.102 AC XY: 7577 AN XY: 74362

African (AFR) AF: 0.214 AC: 8856 AN: 41464

American (AMR) AF: 0.0816 AC: 1246 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0590 AC: 205 AN: 3472

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5180

South Asian (SAS) AF: 0.0376 AC: 181 AN: 4814

European-Finnish (FIN) AF: 0.0573 AC: 607 AN: 10588

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4453 AN: 67998

Other (OTH) AF: 0.105 AC: 222 AN: 2110

Alfa AF: 0.0303 Hom.: 20

Bravo AF: 0.109

Asia WGS AF: 0.0380 AC: 136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.85
DANN	Benign	0.34
PhyloP100		-0.90
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: rs17026452; hg19: chr2-85783765;