rs75861378

Variant names:

• chr8-86654107-A-G
• rs75861378
• NM_019098.5:c.853-45T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_019098.5(CNGB3):​c.853-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,290,418 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (26 hom.)
• Consequence: CNGB3 NM_019098.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.825
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-86654107-A-G is Benign according to our data. Variant chr8-86654107-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 261091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1721/152222) while in subpopulation AFR AF = 0.0392 (1629/41536). AF 95% confidence interval is 0.0376. There are 31 homozygotes in GnomAd4. There are 821 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019098.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	NM_019098.5	MANE Select	c.853-45T>C		intron	N/A	NP_061971.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.853-45T>C		intron	N/A	ENSP00000316605.5	Q9NQW8-1
	CNGB3	ENST00000681546.1		n.673-45T>C		intron	N/A
	CNGB3	ENST00000681746.1		n.853-45T>C		intron	N/A	ENSP00000505959.1	A0A5J6DSN8

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1722 AN: 152104 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

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: 0.000103

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00290 AC: 719 AN: 247754 AF XY: 0.00213

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.00117 AC: 1334 AN: 1138196 Hom.: 26 Cov.: 16 AF XY: 0.00100 AC XY: 582 AN XY: 581862

African (AFR) AF: 0.0414 AC: 1119 AN: 27058

American (AMR) AF: 0.00163 AC: 72 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24074

East Asian (EAS) AF: 0.00 AC: 0 AN: 38058

South Asian (SAS) AF: 0.000126 AC: 10 AN: 79124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52922

Middle Eastern (MID) AF: 0.000390 AC: 2 AN: 5132

European-Non Finnish (NFE) AF: 0.0000342 AC: 28 AN: 818108

Other (OTH) AF: 0.00208 AC: 103 AN: 49602

GnomAD4 genome AF: 0.0113 AC: 1721 AN: 152222 Hom.: 31 Cov.: 32 AF XY: 0.0110 AC XY: 821 AN XY: 74426

African (AFR) AF: 0.0392 AC: 1629 AN: 41536

American (AMR) AF: 0.00458 AC: 70 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68010

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00527 Hom.: 4

Bravo AF: 0.0125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.81
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs75861378; hg19: chr8-87666335;