Genetic Variant GNAQ:p.Gln209Arg (chr9-77794572-T-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_002072.5(GNAQ):c.626A>G(p.Gln209Arg) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q209P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GNAQ
NM_002072.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.02

Publications

476 publications found

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]

GNAQ Gene-Disease associations (from GenCC):

congenital hemangioma
Inheritance: AD Classification: STRONG Submitted by: G2P
Sturge-Weber syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

GNAQ links:

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ACMG classification

Classification was made for transcript

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

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 VariationId 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, congenital hemangioma.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 9-77794572-T-C is Pathogenic according to our data. Variant chr9-77794572-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 375956.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002072.5. 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
	GNAQ	NM_002072.5	MANE Select	c.626A>G	p.Gln209Arg	missense	Exon 5 of 7	NP_002063.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNAQ	ENST00000286548.9	TSL:1 MANE Select	c.626A>G	p.Gln209Arg	missense	Exon 5 of 7	ENSP00000286548.4	P50148
GNAQ	ENST00000857199.1		c.701A>G	p.Gln234Arg	missense	Exon 6 of 8	ENSP00000527258.1
GNAQ	ENST00000915940.1		c.626A>G	p.Gln209Arg	missense	Exon 6 of 8	ENSP00000585999.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Abnormal cardiovascular system morphology (1)

Sturge-Weber syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

8.0

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.85

MutPred

0.90

Gain of MoRF binding (P = 0.0198)

MVP

0.97

MPC

2.6

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

1.0

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over