rs11676382

chr2-85550510-C-G

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+45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,425,082 control chromosomes in the GnomAD database, including 5,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (393 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5361 hom.)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.840

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-85550510-C-G is Benign according to our data. Variant chr2-85550510-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 375657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.2084+45G>C		intron_variant		ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.2084+45G>C		intron_variant		1	NM_000821.7	P1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8924 AN: 152136 Hom.: 393 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0981

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0573 AC: 14316 AN: 249774 Hom.: 560 AF XY: 0.0572 AC XY: 7740 AN XY: 135332

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.0606

Gnomad NFE exome AF: 0.0930

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0858 AC: 109174 AN: 1272828 Hom.: 5361 Cov.: 20 AF XY: 0.0831 AC XY: 53374 AN XY: 642450

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.0419

Gnomad4 EAS exome AF: 0.0000772

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.0614

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0694

GnomAD4 genome AF: 0.0586 AC: 8923 AN: 152254 Hom.: 393 Cov.: 32 AF XY: 0.0541 AC XY: 4030 AN XY: 74454

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0980

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0721 Hom.: 91

Bravo AF: 0.0547

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

GGCX-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.2
Dann	Benign	0.66

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: rs11676382; hg19: chr2-85777633;