rs397515384

Variant names:

• chr1-109608607-C-T
• rs397515384
• NM_001377295.2:c.461+24G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001377295.2(GNAT2):​c.461+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAT2 NM_001377295.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: -1.53
• Publications: 2 publications found

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]

GNAT2 Gene-Disease associations (from GenCC):

• achromatopsia 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• GNAT2-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-109608607-C-T is Pathogenic according to our data. Variant chr1-109608607-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15925.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.461+24G>A		intron_variant	Intron 5 of 8	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.461+24G>A		intron_variant	Intron 5 of 8		NP_001366161.1
GNAT2	NM_005272.5	c.461+24G>A		intron_variant	Intron 4 of 7		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.461+24G>A		intron_variant	Intron 5 of 8		NM_001377295.2	ENSP00000505083.1
GNAT2	ENST00000351050.8	c.461+24G>A		intron_variant	Intron 4 of 7	1		ENSP00000251337.3
GNAT2	ENST00000622865.1	c.*114G>A		downstream_gene_variant		3		ENSP00000482596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Achromatopsia 4 Pathogenic:1 Uncertain:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 12, 2018

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.67
PhyloP100		-1.5
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 3
DS_DL_spliceai		0.41		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515384; hg19: chr1-110151229;