NM_002070.4:c.544A>C

Variant names:

• chr3-50256271-A-C
• NM_002070.4:c.544A>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_002070.4(GNAI2):​c.544A>C​(p.Thr182Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T182I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAI2 NM_002070.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-50256272-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4278646.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.975
• PP5: Variant 3-50256271-A-C is Pathogenic according to our data. Variant chr3-50256271-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1803978.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002070.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAI2	NM_002070.4	MANE Select	c.544A>C	p.Thr182Pro	missense	Exon 5 of 9	NP_002061.1	P04899-1
	GNAI2	NM_001282619.2		c.496A>C	p.Thr166Pro	missense	Exon 6 of 10	NP_001269548.1	P04899-2
	GNAI2	NM_001282620.2		c.496A>C	p.Thr166Pro	missense	Exon 5 of 9	NP_001269549.1	P04899-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAI2	ENST00000313601.11	TSL:1 MANE Select	c.544A>C	p.Thr182Pro	missense	Exon 5 of 9	ENSP00000312999.6	P04899-1
	GNAI2	ENST00000446079.5	TSL:1	n.*179A>C		non_coding_transcript_exon	Exon 6 of 10	ENSP00000406065.1	F8WBG4
	GNAI2	ENST00000446079.5	TSL:1	n.*179A>C		3_prime_UTR	Exon 6 of 10	ENSP00000406065.1	F8WBG4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypopituitarism;C0239989:Decreased circulating total IgM;C0239998:Recurrent infections;C0349588:Short stature;C0520578:Retractile testis;C1854301:Motor delay (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.91		Gain of methylation at K181 (P = 0.1051)
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.99
Mutation Taster		=7/93	disease causing

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

Other links and lift over

hg19: chr3-50293703;