3-50252537-C-T

Position:

• chr3-50252537-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_002070.4(GNAI2):​c.302C>T​(p.Ala101Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,611,744 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (23 hom.)
• Consequence: GNAI2 NM_002070.4 missense, splice_region
• Scores: Splicing: ADA: 0.001634
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.761

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 Benign. Variant got -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0107316375).
• BP6: Variant 3-50252537-C-T is Benign according to our data. Variant chr3-50252537-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 809488.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 380 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAI2	NM_002070.4	c.302C>T	p.Ala101Val	missense_variant, splice_region_variant	3/9	ENST00000313601.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAI2	ENST00000313601.11	c.302C>T	p.Ala101Val	missense_variant, splice_region_variant	3/9	1	NM_002070.4	P1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00255 AC: 634 AN: 248866 Hom.: 5 AF XY: 0.00263 AC XY: 355 AN XY: 134752

Gnomad AFR exome AF: 0.000621

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000902

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00177

Gnomad FIN exome AF: 0.000236

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00341 AC: 4978 AN: 1459444 Hom.: 23 Cov.: 30 AF XY: 0.00341 AC XY: 2473 AN XY: 726038

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.000341

Gnomad4 NFE exome AF: 0.00404

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74466

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00363 Hom.: 1

Bravo AF: 0.00268

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00274 AC: 332

EpiCase AF: 0.00534

EpiControl AF: 0.00594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	GNAI2: PP2, BP4, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	.;.;D;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;T;T;.;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.6	.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.058	T;.;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.083
MVP		0.74
MPC		1.1
ClinPred		0.016	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs112497464; hg19: chr3-50289969;