16-57917490-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001297.5(CNGB1):c.1958-14A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,612,868 control chromosomes in the GnomAD database, including 58,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7595 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51285 hom.)
• Consequence: CNGB1 NM_001297.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.25

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-57917490-T-G is Benign according to our data. Variant chr16-57917490-T-G is described in ClinVar as [Benign]. Clinvar id is 257960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57917490-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGB1	NM_001297.5	c.1958-14A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251102.13
CNGB1	NM_001286130.2	c.1940-14A>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGB1	ENST00000251102.13	c.1958-14A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001297.5	P4
CNGB1	ENST00000564448.5	c.1940-14A>C		splice_polypyrimidine_tract_variant, intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46141 AN: 151748 Hom.: 7580 Cov.: 31

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.271 AC: 67551 AN: 248924 Hom.: 9836 AF XY: 0.274 AC XY: 37005 AN XY: 135114

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.261 AC: 380651 AN: 1461000 Hom.: 51285 Cov.: 35 AF XY: 0.263 AC XY: 190952 AN XY: 726866

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.304 AC: 46199 AN: 151868 Hom.: 7595 Cov.: 31 AF XY: 0.304 AC XY: 22562 AN XY: 74232

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.281

Alfa AF: 0.300 Hom.: 1763

Bravo AF: 0.306

Asia WGS AF: 0.283 AC: 988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis pigmentosa Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.094
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3991715; hg19: chr16-57951394; COSMIC: COSV51897783;