rs17026447

Positions:

• chr2-85550449-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000821.7(GGCX):​c.2084+106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 846,032 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (346 hom., cov: 32)
  • Exomes 𝑓: 0.036 (562 hom.)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.180

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-85550449-A-C is Benign according to our data. Variant chr2-85550449-A-C is described in ClinVar as [Benign]. Clinvar id is 1233214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGCX	NM_000821.7	c.2084+106T>G		intron_variant		ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.2084+106T>G		intron_variant		1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8818 AN: 152130 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0362 AC: 25121 AN: 693784 Hom.: 562 AF XY: 0.0352 AC XY: 12975 AN XY: 368922

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0332

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0000291

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0413

Gnomad4 OTH exome AF: 0.0429

GnomAD4 genome AF: 0.0580 AC: 8832 AN: 152248 Hom.: 346 Cov.: 32 AF XY: 0.0566 AC XY: 4213 AN XY: 74460

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0448

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.0433

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0479 Hom.: 78

Bravo AF: 0.0613

Asia WGS AF: 0.00982 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.54

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: rs17026447; hg19: chr2-85777572;