rs1375507464

Variant names:

• chr8-86604092-C-A
• rs1375507464
• NM_019098.5:c.1781+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-86604092-C-A
• chr8-86604092-C-G
• chr8-86604092-C-T

Variant summary

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

The NM_019098.5(CNGB3):​c.1781+1G>T variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.71

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86604092-C-A is Pathogenic according to our data. Variant chr8-86604092-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 810781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1781+1G>T		splice_donor_variant, intron_variant	Intron 15 of 17	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1367+1G>T		splice_donor_variant, intron_variant	Intron 13 of 15		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1781+1G>T		splice_donor_variant, intron_variant	Intron 15 of 17	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.1601+1G>T		splice_donor_variant, intron_variant	Intron 10 of 12
CNGB3	ENST00000681746.1	n.*192+1G>T		splice_donor_variant, intron_variant	Intron 16 of 18			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia 3;C1855465:Severe early-childhood-onset retinal dystrophy Pathogenic:1

Sep 20, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous 5' splice site variation in intron 15 of the CNGB3 gene that affects the invariant GT donor splice site of exon 15 was detected. A different nucleotide substitution affecting the same splice site (c.1781+1G>C/ c.1781+1G>A) , has previously been reported in patients affected with achromatopsia (Kohl et al. 2005). The observed variant has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, this variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1375507464; hg19: chr8-87616320;