rs759781200
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
Consequence
NM_001379270.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CNGA1 | NM_001379270.1 | c.640C>T | p.Arg214Ter | stop_gained | 10/11 | ENST00000514170.7 | |
LOC101927157 | NR_125879.1 | 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 | c.640C>T | p.Arg214Ter | stop_gained | 10/11 | 5 | NM_001379270.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000987 AC: 15AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248612Hom.: 0 AF XY: 0.0000667 AC XY: 9AN XY: 134860
GnomAD4 exome AF: 0.0000250 AC: 36AN: 1442162Hom.: 0 Cov.: 27 AF XY: 0.0000278 AC XY: 20AN XY: 718820
GnomAD4 genome ? AF: 0.0000987 AC: 15AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74246
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at