19-3121122-C-A

Position:

• chr19-3121122-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM2 PP2 PP3_Strong

The NM_002067.5(GNA11):​c.1023C>A​(p.Phe341Leu) variant causes a missense change involving the alteration of a non-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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_002067.5 (GNA11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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). GenCC has associacion of gene with autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 2, autosomal dominant hypocalcemia 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNA11	NM_002067.5	c.1023C>A	p.Phe341Leu	missense_variant	7/7	ENST00000078429.9	NP_002058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNA11	ENST00000078429.9	c.1023C>A	p.Phe341Leu	missense_variant	7/7	1	NM_002067.5	ENSP00000078429	P1
	ENST00000585980.1	n.466G>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.029
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.018	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.74		Gain of ubiquitination at K345 (P = 0.0931);
MVP		0.94
MPC		2.6
ClinPred		0.99	D
GERP RS		-0.29
Varity_R		0.58
gMVP		0.97

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: chr19-3121120;