NM_001297.5:c.159+14C>T

Variant names:

• chr16-57967114-G-A
• rs199591689
• NM_001297.5:c.159+14C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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
• Publications: 0 publications found

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]

CNGB1 Gene-Disease associations (from GenCC):

• CNGB1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 45

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 257959.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00271 (412/152216) while in subpopulation NFE AF = 0.00481 (327/67988). AF 95% confidence interval is 0.00438. There are 0 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNGB1	NM_001297.5	c.159+14C>T		intron_variant	Intron 2 of 32	ENST00000251102.13	NP_001288.3
CNGB1	NM_001286130.2	c.159+14C>T		intron_variant	Intron 2 of 32		NP_001273059.1
CNGB1	NM_001135639.2	c.159+14C>T		intron_variant	Intron 2 of 12		NP_001129111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNGB1	ENST00000251102.13	c.159+14C>T		intron_variant	Intron 2 of 32	1	NM_001297.5	ENSP00000251102.8

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

GnomAD2 exomes AF: 0.00239 AC: 596 AN: 249452 AF XY: 0.00228

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33476

American (AMR) AF: 0.00280 AC: 125 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53334

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00554 AC: 6161 AN: 1111980

Other (OTH) AF: 0.00348 AC: 210 AN: 60388

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

African (AFR) AF: 0.000867 AC: 36 AN: 41536

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 67988

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00207 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 45 Benign:1

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		-0.13
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199591689; hg19: chr16-58001018;