dbSNP rs137853228: GNAI2:p.Phe200Leu (chr3-50256729-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_002070.4(GNAI2):c.600T>A(p.Phe200Leu) 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).

Frequency

Genomes: not found (cov: 32)

Consequence

GNAI2
NM_002070.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.208

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

ventricular tachycardia, familial
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

GNAI2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.1524 (above the threshold of 3.09). Trascript score misZ: 4.063 (above the threshold of 3.09). GenCC associations: The gene is linked to ventricular tachycardia, familial.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 3-50256729-T-A is Pathogenic according to our data. Variant chr3-50256729-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15906.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAI2	NM_002070.4 link	c.600T>A	p.Phe200Leu	missense_variant	Exon 6 of 9	ENST00000313601.11	NP_002061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAI2	ENST00000313601.11 link	c.600T>A	p.Phe200Leu	missense_variant	Exon 6 of 9	1	NM_002070.4	ENSP00000312999.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ventricular tachycardia, somatic

Pathogenic:1

Jun 15, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

.;.;D;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;.;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.7

.;.;M;.;.

PhyloP100

0.21

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-3.9

D;.;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Benign

0.19

T;T;D;T;T

Polyphen

0.14

.;.;B;.;.

Vest4

0.87

MutPred

0.77

.;.;Loss of catalytic residue at F200 (P = 0.0604);.;.;

MVP

0.96

MPC

1.6

ClinPred

0.99

GERP RS

-0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over