rs121434585

Positions:

• chr1-109610108-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001377295.2(GNAT2):​c.235C>T​(p.Gln79Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAT2 NM_001377295.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.94

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-109610108-G-A is Pathogenic according to our data. Variant chr1-109610108-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15922.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-109610108-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.235C>T	p.Gln79Ter	stop_gained	4/9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.235C>T	p.Gln79Ter	stop_gained	4/9		NP_001366161.1
GNAT2	NM_005272.5	c.235C>T	p.Gln79Ter	stop_gained	3/8		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.235C>T	p.Gln79Ter	stop_gained	4/9		NM_001377295.2	ENSP00000505083	P1
GNAT2	ENST00000351050.8	c.235C>T	p.Gln79Ter	stop_gained	3/8	1		ENSP00000251337	P1
GNAT2	ENST00000622865.1	c.235C>T	p.Gln79Ter	stop_gained	4/5	3		ENSP00000482596

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Jun 12, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GNAT2 are known to be pathogenic (PMID: 12077706). This variant has been observed in individual(s) with achromatopsia (PMID: 12077706). ClinVar contains an entry for this variant (Variation ID: 15922). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln79*) in the GNAT2 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		5.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434585; hg19: chr1-110152730;