rs7568458

Variant names:

• chr2-85561052-T-A
• rs7568458
• NM_000821.7:c.44-67A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-85561052-T-A
• chr2-85561052-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000821.7(GGCX):​c.44-67A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 1,343,042 control chromosomes in the GnomAD database, including 141,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20438 hom., cov: 32)
  • Exomes 𝑓: 0.45 (121162 hom.)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-85561052-T-A is Benign according to our data. Variant chr2-85561052-T-A is described in ClinVar as Benign. ClinVar VariationId is 1277970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.44-67A>T		intron_variant	Intron 1 of 14	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.44-67A>T		intron_variant	Intron 1 of 14	1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76781 AN: 151980 Hom.: 20401 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.447 AC: 531802 AN: 1190944 Hom.: 121162 AF XY: 0.445 AC XY: 269500 AN XY: 605294

African (AFR) AF: 0.689 AC: 19523 AN: 28346

American (AMR) AF: 0.330 AC: 14659 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 9778 AN: 24522

East Asian (EAS) AF: 0.380 AC: 14585 AN: 38402

South Asian (SAS) AF: 0.392 AC: 31731 AN: 81044

European-Finnish (FIN) AF: 0.446 AC: 22497 AN: 50472

Middle Eastern (MID) AF: 0.434 AC: 2279 AN: 5256

European-Non Finnish (NFE) AF: 0.453 AC: 392997 AN: 867144

Other (OTH) AF: 0.462 AC: 23753 AN: 51382

GnomAD4 genome AF: 0.505 AC: 76872 AN: 152098 Hom.: 20438 Cov.: 32 AF XY: 0.502 AC XY: 37291 AN XY: 74336

African (AFR) AF: 0.679 AC: 28186 AN: 41498

American (AMR) AF: 0.408 AC: 6229 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1387 AN: 3472

East Asian (EAS) AF: 0.390 AC: 2016 AN: 5168

South Asian (SAS) AF: 0.391 AC: 1886 AN: 4824

European-Finnish (FIN) AF: 0.453 AC: 4791 AN: 10572

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30791 AN: 67972

Other (OTH) AF: 0.492 AC: 1039 AN: 2112

Alfa AF: 0.345 Hom.: 916

Bravo AF: 0.510

Asia WGS AF: 0.438 AC: 1526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-1.2
PromoterAI		0.0078	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7568458; hg19: chr2-85788175; COSMIC: COSV52088473; COSMIC: COSV52088473;