19-3094694-G-C

Position:

• chr19-3094694-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002067.5(GNA11):​c.43G>C​(p.Val15Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNA11. . Gene score misZ: 3.768 (greater than the threshold 3.09). Trascript score misZ: 3.8723 (greater than threshold 3.09). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 2, autosomal dominant hypocalcemia 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19872305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNA11	NM_002067.5	c.43G>C	p.Val15Leu	missense_variant	1/7	ENST00000078429.9	NP_002058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNA11	ENST00000078429.9	c.43G>C	p.Val15Leu	missense_variant	1/7	1	NM_002067.5	ENSP00000078429.3
GNA11	ENST00000586763.1	n.46G>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.43G>C (p.V15L) alteration is located in exon 1 (coding exon 1) of the GNA11 gene. This alteration results from a G to C substitution at nucleotide position 43, causing the valine (V) at amino acid position 15 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	-0.40	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.31
Sift	Benign	0.044	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.44		Loss of methylation at K16 (P = 0.041);
MVP		0.59
MPC		1.3
ClinPred		0.65	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.68

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: chr19-3094692;