1-109603384-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001377295.2(GNAT2):c.1035A>C(p.Lys345Asn) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAT2	NM_001377295.2	c.1035A>C	p.Lys345Asn	missense_variant	9/9	ENST00000679935.1
GNAT2	NM_001379232.1	c.1035A>C	p.Lys345Asn	missense_variant	9/9
GNAT2	NM_005272.5	c.1035A>C	p.Lys345Asn	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT2	ENST00000679935.1	c.1035A>C	p.Lys345Asn	missense_variant	9/9		NM_001377295.2	P1
GNAT2	ENST00000351050.8	c.1035A>C	p.Lys345Asn	missense_variant	8/8	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Feb 22, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with GNAT2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 345 of the GNAT2 protein (p.Lys345Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.54		Loss of methylation at K345 (P = 0.0068);
MVP		0.88
MPC		1.1
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.85
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-110146006;