rs759781200

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001379270.1(CNGA1):c.640C>T(p.Arg214Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000032 in 1,594,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R214R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CNGA1
NM_001379270.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.75

Variant links:

Genes affected

CNGA1 (HGNC:2148): (cyclic nucleotide gated channel subunit alpha 1) The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]

CNGA1 links:

LOC101927157 (HGNC:):

LOC101927157 links:

NIPAL1 (HGNC:27194): (NIPA like domain containing 1) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

NIPAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-47940775-G-A is Pathogenic according to our data. Variant chr4-47940775-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-47940775-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA1	NM_001379270.1 linkuse as main transcript	c.640C>T	p.Arg214Ter	stop_gained	10/11	ENST00000514170.7
LOC101927157	NR_125879.1 linkuse as main transcript	n.479-18249G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA1	ENST00000514170.7 linkuse as main transcript	c.640C>T	p.Arg214Ter	stop_gained	10/11	5	NM_001379270.1	P1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

248612

Hom.:

AF XY:

0.0000667

AC XY:

AN XY:

134860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000250

AC:

AN:

1442162

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

718820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000769

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000137

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.0000987

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 49

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CNGA1 c.859C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Nov 03, 2022	The c.652C>T;p.Arg218* variant creates a premature translational stop signal in the CNGA1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 242520; PMID: 25326637, PMID: 29785639) - PS4. The variant is present at low allele frequencies population databases (rs759781200 – gnomAD 0.0005714%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Retinitis pigmentosa

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Arg218*) in the CNGA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 473 amino acid(s) of the CNGA1 protein. This variant is present in population databases (rs759781200, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 25326637, 29785639). ClinVar contains an entry for this variant (Variation ID: 242520). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the CNGA1 protein in which other variant(s) (p.Arg424*, p.Arg493*) have been determined to be pathogenic (PMID: 26496393). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D;D;D;D

Vest4

0.96

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over