2-85556005-T-G

Variant names:

• chr2-85556005-T-G
• rs6738645
• NM_000821.7:c.618+177A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000821.7(GGCX):​c.618+177A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,038 control chromosomes in the GnomAD database, including 21,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (21002 hom., cov: 32)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0300
• Publications: 28 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-85556005-T-G is Benign according to our data. Variant chr2-85556005-T-G is described in ClinVar as Benign. ClinVar VariationId is 1221805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.618+177A>C		intron_variant	Intron 5 of 14	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.618+177A>C		intron_variant	Intron 5 of 14	1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77941 AN: 151920 Hom.: 20965 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.513 AC: 78033 AN: 152038 Hom.: 21002 Cov.: 32 AF XY: 0.509 AC XY: 37856 AN XY: 74302

African (AFR) AF: 0.681 AC: 28253 AN: 41462

American (AMR) AF: 0.422 AC: 6445 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3470

East Asian (EAS) AF: 0.391 AC: 2028 AN: 5186

South Asian (SAS) AF: 0.393 AC: 1895 AN: 4824

European-Finnish (FIN) AF: 0.457 AC: 4817 AN: 10536

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31581 AN: 67976

Other (OTH) AF: 0.508 AC: 1073 AN: 2112

Alfa AF: 0.446 Hom.: 6125

Bravo AF: 0.517

Asia WGS AF: 0.438 AC: 1526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.76
CADD	Benign	8.9
DANN	Benign	0.77
PhyloP100		-0.030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6738645; hg19: chr2-85783128;