rs745308973

chr1-109606417-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001377295.2(GNAT2):c.481C>T(p.Arg161Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,742 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GNAT2 NM_001377295.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.486

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 18 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 1-109606417-G-A is Pathogenic according to our data. Variant chr1-109606417-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 522772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-109606417-G-A is described in Lovd as [Pathogenic]. Variant chr1-109606417-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAT2	NM_001377295.2	c.481C>T	p.Arg161Ter	stop_gained	6/9	ENST00000679935.1
GNAT2	NM_001379232.1	c.481C>T	p.Arg161Ter	stop_gained	6/9
GNAT2	NM_005272.5	c.481C>T	p.Arg161Ter	stop_gained	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT2	ENST00000679935.1	c.481C>T	p.Arg161Ter	stop_gained	6/9		NM_001377295.2	P1
GNAT2	ENST00000351050.8	c.481C>T	p.Arg161Ter	stop_gained	5/8	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460598 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726696

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Jun 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 522772). This premature translational stop signal has been observed in individual(s) with GNAT2-related conditions (PMID: 31058429, 31144483). This variant is present in population databases (rs745308973, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Arg161*) in the GNAT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAT2 are known to be pathogenic (PMID: 12077706). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in a patient with cone dystrophy in the literature, although additional clinical information was not provided (Kim et al., 2019); This variant is associated with the following publications: (PMID: 31589614, 31144483, 31058429) -

Achromatopsia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	38
Dann	Uncertain	0.99
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		3.3

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

LitVar

Other links and lift over

dbSNP: rs745308973; hg19: chr1-110149039;