rs199591689

Positions:

• chr16-57967114-G-A
• chr16-57967114-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001297.5(CNGB1):​c.159+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,968 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: CNGB1 NM_001297.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.130

Genes affected

CNGB1 (HGNC:2151): (cyclic nucleotide gated channel subunit beta 1) In humans, the rod photoreceptor cGMP-gated cation channel helps regulate ion flow into the rod photoreceptor outer segment in response to light-induced alteration of the levels of intracellular cGMP. This channel consists of two subunits, alpha and beta, with the protein encoded by this gene representing the beta subunit. Defects in this gene are a cause of cause of retinitis pigmentosa type 45. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-57967114-G-A is Benign according to our data. Variant chr16-57967114-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257959.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr16-57967114-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB1	NM_001297.5	c.159+14C>T		intron_variant		ENST00000251102.13	NP_001288.3
CNGB1	NM_001135639.2	c.159+14C>T		intron_variant			NP_001129111.1
CNGB1	NM_001286130.2	c.159+14C>T		intron_variant			NP_001273059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB1	ENST00000251102.13	c.159+14C>T		intron_variant		1	NM_001297.5	ENSP00000251102	P4

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00239 AC: 596 AN: 249452 Hom.: 0 AF XY: 0.00228 AC XY: 309 AN XY: 135362

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00449 AC: 6557 AN: 1461752 Hom.: 23 Cov.: 31 AF XY: 0.00441 AC XY: 3205 AN XY: 727184

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00554

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74432

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00481

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000973 Hom.: 0

Bravo AF: 0.00294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Retinitis pigmentosa 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs199591689; hg19: chr16-58001018;