1-109603482-G-A

Position:

• chr1-109603482-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001377295.2(GNAT2):​c.937C>T​(p.Arg313Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,454,448 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GNAT2 NM_001377295.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.535

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.12 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-109603482-G-A is Pathogenic according to our data. Variant chr1-109603482-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 623285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-109603482-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.937C>T	p.Arg313Ter	stop_gained	9/9	ENST00000679935.1
GNAT2	NM_001379232.1	c.937C>T	p.Arg313Ter	stop_gained	9/9
GNAT2	NM_005272.5	c.937C>T	p.Arg313Ter	stop_gained	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT2	ENST00000679935.1	c.937C>T	p.Arg313Ter	stop_gained	9/9		NM_001377295.2	P1
GNAT2	ENST00000351050.8	c.937C>T	p.Arg313Ter	stop_gained	8/8	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251362 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1454448 Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 13 AN XY: 724014

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000814

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achromatopsia 4 (MIM#613856). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0601 - Variant results in the loss of the well-established functional GTP binding domain, conserved motif and GTP, Mg2+ and receptor-binding residues (NCBI domains, PMID: 31058429, PMID: 18643908). (I) 0704 - Other protein truncation variants comparable to the one identified in this case has limited previous evidence for pathogenicity. One variant, p.(Ile319fs*5), has been reported as pathogenic and observed in compound heterozygous siblings with achromatopsia (PMID: 31058429, ClinVar). p.(Tyr320*) has been reported as pathogenic (LOVD). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and observed in two unrelated homozygous individuals with congenital achromatopsia or cone dystrophy, and a compound heterozygous individual with achromatopsia (ClinVar, PMID: 21107338, PMID: 27208204, PMID: 31058429). (SP) 0906 - Segregation evidence for this variant is inconclusive. Segregation testing demonstrated that all affected individuals in a large family shared the same homozygous haplotype, whereas unaffected relatives did not. These findings were considered inconclusive (PMID: 21107338). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely 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

Nov 08, 2023

This sequence change creates a premature translational stop signal (p.Arg313*) in the GNAT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the GNAT2 protein. This variant is present in population databases (rs748981899, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 21107338). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 623285). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	D
Vest4		0.81
GERP RS		-2.1

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: rs748981899; hg19: chr1-110146104;