3-50256262-C-T

Position:

• chr3-50256262-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002070.4(GNAI2):​c.535C>T​(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNAI2 NM_002070.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:3 U:2
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a modified_residue ADP-ribosylarginine; by cholera toxin (size 0) in uniprot entity GNAI2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAI2	NM_002070.4	c.535C>T	p.Arg179Cys	missense_variant	5/9	ENST00000313601.11	NP_002061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAI2	ENST00000313601.11	c.535C>T	p.Arg179Cys	missense_variant	5/9	1	NM_002070.4	ENSP00000312999.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460128 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Thecoma, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 10, 1990

- -

Ovarian granulosa cell tumor Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 10, 1990

- -

Adrenocortical tumor, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 10, 1990

- -

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	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.5	.;.;H;.;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.91
MutPred		0.88		.;.;Loss of catalytic residue at R179 (P = 0.0057);.;.;
MVP		0.91
MPC		1.4
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs137853226; hg19: chr3-50293694; COSMIC: COSV56492973; COSMIC: COSV56492973;