rs147528229

chr19-3110205-G-Achr19-3110205-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002067.5(GNA11):c.193G>A(p.Ala65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00092 in 1,613,616 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A65A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0590

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GNA11
• BP4: Computational evidence support a benign effect (MetaRNN=0.012868196).
• BP6: Variant 19-3110205-G-A is Benign according to our data. Variant chr19-3110205-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00506 (770/152194) while in subpopulation AFR AF= 0.018 (746/41526). AF 95% confidence interval is 0.0169. There are 9 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNA11	NM_002067.5	c.193G>A	p.Ala65Thr	missense_variant	2/7	ENST00000078429.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNA11	ENST00000078429.9	c.193G>A	p.Ala65Thr	missense_variant	2/7	1	NM_002067.5	P1
GNA11	ENST00000586763.1	n.140-3125G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152076 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00127 AC: 318 AN: 249994 Hom.: 1 AF XY: 0.000952 AC XY: 129 AN XY: 135482

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000489 AC: 714 AN: 1461422 Hom.: 3 Cov.: 32 AF XY: 0.000406 AC XY: 295 AN XY: 727014

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00506 AC: 770 AN: 152194 Hom.: 9 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74396

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00566

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	See Variant Classification Assertion Criteria. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.040	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.36
MPC		1.3
ClinPred		0.0035	T
GERP RS		0.95
Varity_R		0.059
gMVP		0.79

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: rs147528229; hg19: chr19-3110203; COSMIC: COSV50018023; COSMIC: COSV50018023;