2-85560218-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.214+597G>A		intron_variant		ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.214+597G>A		intron_variant		1	NM_000821.7	P1

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

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.342

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.402

Alfa AF: 0.402 Hom.: 3435

Bravo AF: 0.408

Asia WGS AF: 0.401 AC: 1392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.7
Dann	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs12714145; hg19: chr2-85787341;