2-85545425-C-T

Position:

• chr2-85545425-C-T

Variant summary

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

The ENST00000233838.9(GGCX):​c.*4509G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 152,128 control chromosomes in the GnomAD database, including 21,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21084 hom., cov: 32)
  • Exomes 𝑓: 0.46 (15 hom.)
• Consequence: GGCX ENST00000233838.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.876

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=-0.81).
• BP6: Variant 2-85545425-C-T is Benign according to our data. Variant chr2-85545425-C-T is described in ClinVar as [Benign]. Clinvar id is 337179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGCX	NM_000821.7	c.*4509G>A		3_prime_UTR_variant	15/15	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.*4509G>A		3_prime_UTR_variant	15/15	1	NM_000821.7	ENSP00000233838	P1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78047 AN: 151850 Hom.: 21044 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.456 AC: 73 AN: 160 Hom.: 15 Cov.: 0 AF XY: 0.480 AC XY: 49 AN XY: 102

Gnomad4 FIN exome AF: 0.462

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.514 AC: 78143 AN: 151968 Hom.: 21084 Cov.: 32 AF XY: 0.510 AC XY: 37908 AN XY: 74264

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.422

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.508

Alfa AF: 0.491 Hom.: 2364

Bravo AF: 0.518

Asia WGS AF: 0.439 AC: 1530 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.42
DANN	Benign	0.46

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: rs7605975; hg19: chr2-85772548;