3-50256262-C-T

Variant names:

• chr3-50256262-C-T
• rs137853226
• NM_002070.4:c.535C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:3 U:2
• Conservation: PhyloP100: 2.08
• Publications: 11 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 10 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 VariationId is 15905.Status of the report is no_assertion_criteria_provided, 0 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, 0.967
• PP5: Variant 3-50256262-C-T is Pathogenic according to our data. Variant chr3-50256262-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15903.Status of the report is no_assertion_criteria_provided, 0 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.535C>T	p.Arg179Cys	missense	Exon 5 of 9	NP_002061.1	P04899-1
	GNAI2	NM_001282619.2		c.487C>T	p.Arg163Cys	missense	Exon 6 of 10	NP_001269548.1	P04899-2
	GNAI2	NM_001282620.2		c.487C>T	p.Arg163Cys	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.535C>T	p.Arg179Cys	missense	Exon 5 of 9	ENSP00000312999.6	P04899-1
	GNAI2	ENST00000446079.5	TSL:1	n.*170C>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000406065.1	F8WBG4
	GNAI2	ENST00000446079.5	TSL:1	n.*170C>T		3_prime_UTR	Exon 6 of 10	ENSP00000406065.1	F8WBG4

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

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110456

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	Adrenocortical tumor, somatic (1)
1	-	-	Ovarian granulosa cell tumor (1)
1	-	-	Thecoma, somatic (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		2.1
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=0/100	disease causing (ClinVar)

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

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