chr8-86643875-T-A

Variant names:

• chr8-86643875-T-A
• NM_019098.5:c.1056-2A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_019098.5(CNGB3):​c.1056-2A>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNGB3 NM_019098.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.050617285 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1056-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 17	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.642-2A>T		splice_acceptor_variant, intron_variant	Intron 7 of 15		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1056-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 17	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.876-2A>T		splice_acceptor_variant, intron_variant	Intron 4 of 12
CNGB3	ENST00000681746.1	n.1056-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 18			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.97		Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-87656103;