chr3-50256262-C-G

Position:

• chr3-50256262-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_002070.4(GNAI2):​c.535C>G​(p.Arg179Gly) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI2 NM_002070.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.08

Genes affected

GNAI2 (HGNC:4385): (G protein subunit alpha i2) The protein encoded by this gene is an alpha subunit of guanine nucleotide binding proteins (G proteins). The encoded protein contains the guanine nucleotide binding site and is involved in the hormonal regulation of adenylate cyclase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-50256263-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15904.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAI2. . Gene score misZ 3.1524 (greater than the threshold 3.09). Trascript score misZ 4.063 (greater than threshold 3.09). GenCC has associacion of gene with ventricular tachycardia, familial.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 3-50256262-C-G is Pathogenic according to our data. Variant chr3-50256262-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15905.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI2	NM_002070.4	c.535C>G	p.Arg179Gly	missense_variant	5/9	ENST00000313601.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI2	ENST00000313601.11	c.535C>G	p.Arg179Gly	missense_variant	5/9	1	NM_002070.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pituitary dependent hypercortisolism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1995

- -

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	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.5	.;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.94
MutPred		0.87		.;.;Loss of catalytic residue at R179 (P = 0.004);.;.;
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853226; hg19: chr3-50293694;