rs1554607548

Variant names:

• chr8-86604099-T-TC
• rs1554607548
• NM_019098.5:c.1774dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_019098.5(CNGB3):​c.1774dupG​(p.Glu592GlyfsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNGB3 NM_019098.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.71
• 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-86604099-T-TC is Pathogenic according to our data. Variant chr8-86604099-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 557186.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.1774dupG	p.Glu592GlyfsTer44	frameshift_variant	Exon 15 of 18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1360dupG	p.Glu454GlyfsTer44	frameshift_variant	Exon 13 of 16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1774dupG	p.Glu592GlyfsTer44	frameshift_variant	Exon 15 of 18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.1594dupG		non_coding_transcript_exon_variant	Exon 10 of 13
CNGB3	ENST00000681746.1	n.*185dupG		non_coding_transcript_exon_variant	Exon 16 of 19			ENSP00000505959.1
CNGB3	ENST00000681746.1	n.*185dupG		3_prime_UTR_variant	Exon 16 of 19			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453526 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723744

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104516

Other (OTH) AF: 0.00 AC: 0 AN: 60092

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia 3 Pathogenic:1

Mar 12, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557186). This premature translational stop signal has been observed in individual(s) with CNGB3-related conditions (PMID: 23776498). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu592Glyfs*44) in the CNGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 28795510). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554607548; hg19: chr8-87616327;