chr2-85550449-A-C

Variant names:

• chr2-85550449-A-C
• rs17026447
• NM_000821.7:c.2084+106T>G

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.2084+106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 846,032 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (346 hom., cov: 32)
  • Exomes 𝑓: 0.036 (562 hom.)
• Consequence: GGCX NM_000821.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.180
• Publications: 2 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 2-85550449-A-C is Benign according to our data. Variant chr2-85550449-A-C is described in ClinVar as Benign. ClinVar VariationId is 1233214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.2084+106T>G		intron_variant	Intron 14 of 14	ENST00000233838.9	NP_000812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.2084+106T>G		intron_variant	Intron 14 of 14	1	NM_000821.7	ENSP00000233838.3

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8818 AN: 152130 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0362 AC: 25121 AN: 693784 Hom.: 562 AF XY: 0.0352 AC XY: 12975 AN XY: 368922

African (AFR) AF: 0.107 AC: 1994 AN: 18684

American (AMR) AF: 0.0332 AC: 1236 AN: 37192

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 676 AN: 21056

East Asian (EAS) AF: 0.0000291 AC: 1 AN: 34412

South Asian (SAS) AF: 0.0133 AC: 904 AN: 67994

European-Finnish (FIN) AF: 0.0202 AC: 992 AN: 49162

Middle Eastern (MID) AF: 0.0576 AC: 191 AN: 3314

European-Non Finnish (NFE) AF: 0.0413 AC: 17630 AN: 427090

Other (OTH) AF: 0.0429 AC: 1497 AN: 34880

GnomAD4 genome AF: 0.0580 AC: 8832 AN: 152248 Hom.: 346 Cov.: 32 AF XY: 0.0566 AC XY: 4213 AN XY: 74460

African (AFR) AF: 0.113 AC: 4674 AN: 41530

American (AMR) AF: 0.0448 AC: 685 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4822

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10622

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2943 AN: 68012

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0474 Hom.: 138

Bravo AF: 0.0613

Asia WGS AF: 0.00982 AC: 36 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	0.54
PhyloP100		-0.18
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: rs17026447; hg19: chr2-85777572;