rs200638562
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_206933.4(USH2A):c.2167+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_206933.4 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- Usher syndrome type 2Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Usher syndrome type 2AInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- retinitis pigmentosa 39Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- retinitis pigmentosaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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USH2A | ENST00000307340.8 | c.2167+4C>T | splice_region_variant, intron_variant | Intron 12 of 71 | 1 | NM_206933.4 | ENSP00000305941.3 | |||
USH2A | ENST00000366942.3 | c.2167+4C>T | splice_region_variant, intron_variant | Intron 12 of 20 | 1 | ENSP00000355909.3 | ||||
USH2A | ENST00000674083.1 | c.2167+4C>T | splice_region_variant, intron_variant | Intron 12 of 72 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250446 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461490Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727060 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant classified as Uncertain Significance - Favor Benign. The 2167+4C>T varia nt in USH2A has not been reported in the literature nor previously identified by our laboratory. This variant is located in the 5' splice region but does not af fect the invariant +1 and +2 positions. Although position +4 is part of the spli ce site region, the reference sequence was already divergent from consensus (nor mally an A at this position) and therefore this variant is less likely to disrup t splicing. In summary, the clinical significance of this variant cannot be dete rmined with certainty at this time; however, given that there is currently no ev idence to suggest this variant is pathogenic, we would lean towards a more likel y benign role. -
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Usher syndrome type 2A Uncertain:2
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Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Uncertain:1
This sequence change falls in intron 12 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200638562, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48485). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Retinitis pigmentosa 39 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at