2-85545505-C-T

Position:

• chr2-85545505-C-T

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.*4429G>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 0.113 in 152,198 control chromosomes in the GnomAD database, including 1,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1009 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GGCX NM_000821.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.317

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=-0.8).
• BP6: Variant 2-85545505-C-T is Benign according to our data. Variant chr2-85545505-C-T is described in ClinVar as [Benign]. Clinvar id is 337180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGCX	NM_000821.7	c.*4429G>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.*4429G>A		3_prime_UTR_variant	15/15	1	NM_000821.7	ENSP00000233838	P1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17119 AN: 152080 Hom.: 1008 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.124

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.113 AC: 17130 AN: 152198 Hom.: 1009 Cov.: 33 AF XY: 0.113 AC XY: 8419 AN XY: 74416

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0595

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.0788

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.122

Alfa AF: 0.121 Hom.: 289

Bravo AF: 0.113

Asia WGS AF: 0.122 AC: 425 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 13, 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	-0.80
CADD	Benign	1.2
DANN	Benign	0.40

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: rs62165899; hg19: chr2-85772628;