8-86629002-A-G

Position:

• chr8-86629002-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000320005.6(CNGB3):​c.1397T>C​(p.Met466Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,042 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M466K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0091 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (15 hom.)
• Consequence: CNGB3 ENST00000320005.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 9.32

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 Benign. Variant got -17 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-86629002-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427675.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.012754291).
• BP6: Variant 8-86629002-A-G is Benign according to our data. Variant chr8-86629002-A-G is described in ClinVar as [Benign]. Clinvar id is 261083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86629002-A-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00913 (1390/152282) while in subpopulation AFR AF= 0.0316 (1315/41570). AF 95% confidence interval is 0.0302. There are 19 homozygotes in gnomad4. There are 677 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1397T>C	p.Met466Thr	missense_variant	12/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.983T>C	p.Met328Thr	missense_variant	10/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1397T>C	p.Met466Thr	missense_variant	12/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681546.1	n.1217T>C		non_coding_transcript_exon_variant	7/13
CNGB3	ENST00000681746.1	c.1397T>C	p.Met466Thr	missense_variant, NMD_transcript_variant	12/19			ENSP00000505959

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1392 AN: 152164 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00225 AC: 566 AN: 251056 Hom.: 5 AF XY: 0.00162 AC XY: 220 AN XY: 135650

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000880 AC: 1287 AN: 1461760 Hom.: 15 Cov.: 32 AF XY: 0.000747 AC XY: 543 AN XY: 727178

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00913 AC: 1390 AN: 152282 Hom.: 19 Cov.: 32 AF XY: 0.00909 AC XY: 677 AN XY: 74458

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00109 Hom.: 3

Bravo AF: 0.0103

ESP6500AA AF: 0.0320 AC: 141

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Achromatopsia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 06, 2020

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.97
MVP		1.0
MPC		0.19
ClinPred		0.083	T
GERP RS		5.9
Varity_R		0.82
gMVP		0.95

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: rs35010099; hg19: chr8-87641230;