chr9-77794572-T-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_002072.5(GNAQ):​c.626A>C​(p.Gln209Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q209H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GNAQ
NM_002072.5 missense

Scores

15
2
2

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 8.02
Variant links:
Genes affected
GNAQ (HGNC:4390): (G protein subunit alpha q) This locus encodes a guanine nucleotide-binding protein. The encoded protein, an alpha subunit in the Gq class, couples a seven-transmembrane domain receptor to activation of phospolipase C-beta. Mutations at this locus have been associated with problems in platelet activation and aggregation. A related pseudogene exists on chromosome 2.[provided by RefSeq, Nov 2010]

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1
In a modified_residue 5-glutamyl histamine (size 0) in uniprot entity GNAQ_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002072.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-77794571-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1172602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6575 (above the threshold of 3.09). Trascript score misZ: 2.6566 (below the threshold of 3.09). GenCC associations: The gene is linked to Sturge-Weber syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNAQNM_002072.5 linkc.626A>C p.Gln209Pro missense_variant Exon 5 of 7 ENST00000286548.9 NP_002063.2 P50148A0A024R240
GNAQXM_047423239.1 linkc.452A>C p.Gln151Pro missense_variant Exon 5 of 7 XP_047279195.1
GNAQXM_047423240.1 linkc.452A>C p.Gln151Pro missense_variant Exon 5 of 7 XP_047279196.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNAQENST00000286548.9 linkc.626A>C p.Gln209Pro missense_variant Exon 5 of 7 1 NM_002072.5 ENSP00000286548.4 P50148

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Uveal melanoma Pathogenic:1
Jul 14, 2015
Database of Curated Mutations (DoCM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Melanoma Pathogenic:1
Oct 02, 2014
Database of Curated Mutations (DoCM)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.76
T
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H
PhyloP100
8.0
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.90
MutPred
0.87
Loss of catalytic residue at Q209 (P = 0.0135);
MVP
0.96
MPC
2.7
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.98
gMVP
1.0
Mutation Taster
=11/89
disease causing (ClinVar)

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

Publications

Other links and lift over

dbSNP: rs121913492; hg19: chr9-80409488; COSMIC: COSV54105903; COSMIC: COSV54105903; API