2-85545505-C-T

Variant names:

• chr2-85545505-C-T
• rs62165899
• NM_000821.7:c.*4429G>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.*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
• Publications: 4 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=-0.8).
• BP6: Variant 2-85545505-C-T is Benign according to our data. Variant chr2-85545505-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.*4429G>A		3_prime_UTR	Exon 15 of 15	NP_000812.2
	GGCX	NM_001142269.4		c.*4429G>A		3_prime_UTR	Exon 14 of 14	NP_001135741.1	P38435-2
	MAT2A	NM_005911.6	MANE Select	c.*1733C>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.*4429G>A		3_prime_UTR	Exon 15 of 15	ENSP00000233838.3	P38435-1
	MAT2A	ENST00000306434.8	TSL:1 MANE Select	c.*1733C>T		downstream_gene	N/A	ENSP00000303147.3	P31153-1
	MAT2A	ENST00000881374.1		c.*1733C>T		downstream_gene	N/A	ENSP00000551433.1

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

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

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

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.107 AC: 4457 AN: 41494

American (AMR) AF: 0.115 AC: 1758 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3472

East Asian (EAS) AF: 0.0595 AC: 309 AN: 5192

South Asian (SAS) AF: 0.186 AC: 895 AN: 4820

European-Finnish (FIN) AF: 0.0788 AC: 834 AN: 10590

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8080 AN: 68018

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.120 Hom.: 511

Bravo AF: 0.113

Asia WGS AF: 0.122 AC: 425 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	-0.80
CADD	Benign	1.2
DANN	Benign	0.40
PhyloP100		0.32
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: rs62165899; hg19: chr2-85772628;