NM_002067.5:c.626A>C

Variant names:

• chr19-3118944-A-C
• rs1057519742
• NM_002067.5:c.626A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_002067.5(GNA11):​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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• 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 Likely_pathogenic. Variant got 9 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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNA11	NM_002067.5	c.626A>C	p.Gln209Pro	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>C	p.Gln209Pro	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/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

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	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.88		Loss of catalytic residue at Q209 (P = 0.016);
MVP		0.95
MPC		2.0
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs1057519742; hg19: chr19-3118942; COSMIC: COSV50017882; COSMIC: COSV50017882;