9-77728541-G-C

Variant names:

• chr9-77728541-G-C
• rs886255565
• NM_002072.5:c.862C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002072.5(GNAQ):​c.862C>G​(p.Leu288Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,452,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L288I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.862C>G	p.Leu288Val	missense	Exon 6 of 7	NP_002063.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAQ	ENST00000286548.9	TSL:1 MANE Select	c.862C>G	p.Leu288Val	missense	Exon 6 of 7	ENSP00000286548.4	P50148
	GNAQ	ENST00000857199.1		c.937C>G	p.Leu313Val	missense	Exon 7 of 8	ENSP00000527258.1
	GNAQ	ENST00000915940.1		c.862C>G	p.Leu288Val	missense	Exon 7 of 8	ENSP00000585999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452680 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 723326

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4814

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104590

Other (OTH) AF: 0.00 AC: 0 AN: 60054

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.028	D
Polyphen		0.017	B
Vest4		0.56
MutPred		0.63		Loss of catalytic residue at L288 (P = 0.0722)
MVP		0.93
MPC		1.6
ClinPred		0.73	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.97
Mutation Taster		=60/40	polymorphism

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: rs886255565; hg19: chr9-80343457;