2-85545425-C-T

Variant names:

• chr2-85545425-C-T
• rs7605975
• NM_000821.7:c.*4509G>A

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.*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 NM_000821.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.876
• Publications: 23 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]

MAT2A (HGNC:6904): (methionine adenosyltransferase 2A) The protein encoded by this gene catalyzes the production of S-adenosylmethionine (AdoMet) from methionine and ATP. AdoMet is the key methyl donor in cellular processes. [provided by RefSeq, Jun 2011]

MAT2A Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000821.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCX	NM_000821.7	MANE Select	c.*4509G>A		3_prime_UTR	Exon 15 of 15	NP_000812.2
	GGCX	NM_001142269.4		c.*4509G>A		3_prime_UTR	Exon 14 of 14	NP_001135741.1	P38435-2
	MAT2A	NM_005911.6	MANE Select	c.*1653C>T		downstream_gene	N/A	NP_005902.1	P31153-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCX	ENST00000233838.9	TSL:1 MANE Select	c.*4509G>A		3_prime_UTR	Exon 15 of 15	ENSP00000233838.3	P38435-1
	MAT2A	ENST00000306434.8	TSL:1 MANE Select	c.*1653C>T		downstream_gene	N/A	ENSP00000303147.3	P31153-1
	MAT2A	ENST00000881374.1		c.*1653C>T		downstream_gene	N/A	ENSP00000551433.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.462 AC: 73 AN: 158

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.685 AC: 28394 AN: 41438

American (AMR) AF: 0.422 AC: 6441 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1390 AN: 3466

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

South Asian (SAS) AF: 0.391 AC: 1888 AN: 4824

European-Finnish (FIN) AF: 0.457 AC: 4813 AN: 10524

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

European-Non Finnish (NFE) AF: 0.465 AC: 31576 AN: 67956

Other (OTH) AF: 0.508 AC: 1074 AN: 2116

Alfa AF: 0.500 Hom.: 2558

Bravo AF: 0.518

Asia WGS AF: 0.439 AC: 1530 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.42
DANN	Benign	0.46
PhyloP100		-0.88
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: rs7605975; hg19: chr2-85772548;