rs3738766

chr1-109608773-G-Cchr1-109608773-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001377295.2(GNAT2):c.319C>G(p.Leu107Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L107I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.06

Genes affected

GNAT2 (HGNC:4394): (G protein subunit alpha transducin 2) Transducin is a 3-subunit guanine nucleotide-binding protein (G protein) which stimulates the coupling of rhodopsin and cGMP-phoshodiesterase during visual impulses. The transducin alpha subunits in rods and cones are encoded by separate genes. This gene encodes the alpha subunit in cones. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAT2	NM_001377295.2	c.319C>G	p.Leu107Val	missense_variant	5/9	ENST00000679935.1
GNAT2	NM_001379232.1	c.319C>G	p.Leu107Val	missense_variant	5/9
GNAT2	NM_005272.5	c.319C>G	p.Leu107Val	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT2	ENST00000679935.1	c.319C>G	p.Leu107Val	missense_variant	5/9		NM_001377295.2	P1
GNAT2	ENST00000351050.8	c.319C>G	p.Leu107Val	missense_variant	4/8	1		P1
GNAT2	ENST00000622865.1	c.319C>G	p.Leu107Val	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNAT2 protein function. ClinVar contains an entry for this variant (Variation ID: 1041462). This variant has not been reported in the literature in individuals affected with GNAT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 107 of the GNAT2 protein (p.Leu107Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	8.6e-8	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N;.
REVEL	Uncertain	0.44
Sift	Benign	0.31	T;.
Sift4G	Benign	0.42	T;.
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.35		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.94
MPC		0.39
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.44
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs3738766; hg19: chr1-110151395;