Variant chr3-50256262-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GNAI2
NM_002070.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:3U:2

Conservation

PhyloP100: 2.08

Variant links:

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]

GNAI2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-50256262-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15905.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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI2	NM_002070.4 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	5/9	ENST00000313601.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI2	ENST00000313601.11 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	5/9	1	NM_002070.4	P1	P04899-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460128

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726536

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:2

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

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

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;.;D;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

D;D;D;.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

4.5

.;.;H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.96

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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