rs769001387
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_206933.4(USH2A):āc.12580T>Cā(p.Cys4194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C4194Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12580T>C | p.Cys4194Arg | missense_variant | 63/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12580T>C | p.Cys4194Arg | missense_variant | 63/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.12580T>C | p.Cys4194Arg | missense_variant | 63/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134996
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461802Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2AN XY: 727196
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809) and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 3 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated Fibronectin type III domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Cys4194Tyr) has been regarded as a VUS by multiple clinical laboratories in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Even though it has been reported as a VUS (ClinVar, PMID: 33124170), this variant has been reported as likely pathogenic (ClinVar) and detected in multiple individuals with retinitis pigmentosa (PMIDs: 25649381, 30029497, 34315337, 33124170). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 4194 of the USH2A protein (p.Cys4194Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25649381, 30029497, 33090715, 33124170; Invitae). ClinVar contains an entry for this variant (Variation ID: 557093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 07, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at