8-86604201-C-A

Position:

• chr8-86604201-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_019098.5(CNGB3):​c.1673G>T​(p.Gly558Val) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G558C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-86604202-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1673G>T	p.Gly558Val	missense_variant	15/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.1259G>T	p.Gly420Val	missense_variant	13/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1673G>T	p.Gly558Val	missense_variant	15/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681546.1	n.1493G>T		non_coding_transcript_exon_variant	10/13
CNGB3	ENST00000681746.1	c.*84G>T		3_prime_UTR_variant, NMD_transcript_variant	16/19			ENSP00000505959

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Uncertain:2

Uncertain significance, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -

Achromatopsia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Mar 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Gain of methylation at K559 (P = 0.0394);
MVP		1.0
MPC		0.24
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1262707163; hg19: chr8-87616429;