chr8-86604216-A-C

Variant names:

• chr8-86604216-A-C
• rs964530890
• NM_019098.5:c.1663-5T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_019098.5(CNGB3):​c.1663-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,396,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNGB3 NM_019098.5 splice_region, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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]

CNGB3 Gene-Disease associations (from GenCC):

• achromatopsia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• CNGB3-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
• severe early-childhood-onset retinal dystrophy

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-86604216-A-C is Pathogenic according to our data. Variant chr8-86604216-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 427706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86604216-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 427706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1663-5T>G		splice_region_variant, intron_variant	Intron 14 of 17	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1249-5T>G		splice_region_variant, intron_variant	Intron 12 of 15		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1663-5T>G		splice_region_variant, intron_variant	Intron 14 of 17	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.1483-5T>G		splice_region_variant, intron_variant	Intron 9 of 12
CNGB3	ENST00000681746.1	n.*74-5T>G		splice_region_variant, intron_variant	Intron 15 of 18			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396956 Hom.: 0 Cov.: 23 AF XY: 0.00000143 AC XY: 1 AN XY: 698986

African (AFR) AF: 0.00 AC: 0 AN: 32184

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.00 AC: 0 AN: 84726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1053198

Other (OTH) AF: 0.0000172 AC: 1 AN: 58186

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:2

Mar 27, 2017

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 16319819). ClinVar contains an entry for this variant (Variation ID: 427706). This variant has been observed in individual(s) with achromatopsia (PMID: 16319819, 28795510). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change falls in intron 14 of the CNGB3 gene. It does not directly change the encoded amino acid sequence of the CNGB3 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.41
PhyloP100		1.6
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -1
DS_AL_spliceai		0.83		Position offset: -5

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

Other links and lift over

dbSNP: rs964530890; hg19: chr8-87616444;