NM_002067.5:c.626A>G

Variant names:

• chr19-3118944-A-G
• NM_002067.5:c.626A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_002067.5(GNA11):​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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.14

Genes affected

GNA11 (HGNC:4379): (G protein subunit alpha 11) The protein encoded by this gene belongs to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes one of the alpha subunits (subunit alpha-11). Mutations in this gene have been associated with hypocalciuric hypercalcemia type II (HHC2) and hypocalcemia dominant 2 (HYPOC2). Patients with HHC2 and HYPOC2 exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. [provided by RefSeq, Dec 2013]

ENSG00000267139 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a modified_residue Deamidated glutamine; by Photorhabdus PAU_02230 (size 0) in uniprot entity GNA11_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GNA11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.768 (above the threshold of 3.09). Trascript score misZ: 3.8723 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 2, autosomal dominant hypocalcemia 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-3118944-A-G is Pathogenic according to our data. Variant chr19-3118944-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1691369.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNA11	NM_002067.5	c.626A>G	p.Gln209Arg	missense_variant	Exon 5 of 7	ENST00000078429.9	NP_002058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNA11	ENST00000078429.9	c.626A>G	p.Gln209Arg	missense_variant	Exon 5 of 7	1	NM_002067.5	ENSP00000078429.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 10, 2022

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alteration of p.Gln209 in GNAQ is a recurrent oncogenic hotspot reported in the cBioPortal and NCI Genomic Data Commons cancer databases. This variant is absent from large population studies as a germline finding (Genome Aggregation Database v2.1.1). To our knowledge, this variant has not been reported in association with capillary malformations (CM) before, but somatic mutations altering amino acid residue p.Gln209 have been described in congenital hemangioma (PMID: 27058448). Somatic mutations altering amino acid residue p.Arg183 are known to cause capillary malformations (PMID: 30870248, PMID: 26368330, PMID: 29174369). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.88
MutPred		0.91		Gain of MoRF binding (P = 0.0172);
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.92
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-3118942; COSMIC: COSV50017623; COSMIC: COSV50017623;