chr8-86654023-T-C

Position:

• chr8-86654023-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_019098.5(CNGB3):​c.892A>G​(p.Thr298Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T298P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGB3 NM_019098.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 30) in uniprot entity CNGB3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_019098.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14869046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.892A>G	p.Thr298Ala	missense_variant	7/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.478A>G	p.Thr160Ala	missense_variant	5/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.892A>G	p.Thr298Ala	missense_variant	7/18	1	NM_019098.5	ENSP00000316605.5
CNGB3	ENST00000681546.1	n.712A>G		non_coding_transcript_exon_variant	2/13
CNGB3	ENST00000681746.1	n.892A>G		non_coding_transcript_exon_variant	7/19			ENSP00000505959.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.74	T
Sift4G	Benign	0.75	T
Polyphen		0.027	B
Vest4		0.27
MutPred		0.55		Gain of methylation at R295 (P = 0.1022);
MVP		0.45
MPC		0.029
ClinPred		0.18	T
GERP RS		4.2
Varity_R		0.077
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4961206; hg19: chr8-87666251;