3-50256729-T-A

Position:

• chr3-50256729-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.208

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.879
• PP5: Variant 3-50256729-T-A is Pathogenic according to our data. Variant chr3-50256729-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15906.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.600T>A	p.Phe200Leu	missense_variant	6/9	ENST00000313601.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI2	ENST00000313601.11	c.600T>A	p.Phe200Leu	missense_variant	6/9	1	NM_002070.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ventricular tachycardia, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	.;.;D;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D;.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.96	D
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	D
GERP RS		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs137853228; hg19: chr3-50294161;