rs587777020

Variant names:

• chr19-3115009-G-A
• rs587777020
• NM_002067.5:c.542G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-3115009-G-A
• chr19-3115009-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_002067.5(GNA11):​c.542G>A​(p.Arg181Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 9.81

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNA11	NM_002067.5	c.542G>A	p.Arg181Gln	missense_variant	Exon 4 of 7	ENST00000078429.9	NP_002058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNA11	ENST00000078429.9	c.542G>A	p.Arg181Gln	missense_variant	Exon 4 of 7	1	NM_002067.5	ENSP00000078429.3
GNA11	ENST00000587636.1	c.86G>A	p.Arg29Gln	missense_variant	Exon 2 of 6	5		ENSP00000465935.1
GNA11	ENST00000588401.1	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 2	2		ENSP00000479797.1
GNA11	ENST00000586763.1	n.*6G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00460 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant hypocalcemia 2 Pathogenic:2

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 27, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects GNA11 function (PMID: 23802516, 26994139). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 60663). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia, type 2 (PMID: 23802516). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 181 of the GNA11 protein (p.Arg181Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.83		Loss of sheet (P = 0.0817);
MVP		0.93
MPC		2.7
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777020; hg19: chr19-3115007;