chr10-54317272-G-C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_033056.4(PCDH15):c.875C>G(p.Pro292Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P292L) has been classified as Uncertain significance.
Frequency
Consequence
NM_033056.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 23Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
- Usher syndrome type 1Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Usher syndrome type 1FInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- nonsyndromic genetic hearing lossInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.875C>G | p.Pro292Arg | missense_variant, splice_region_variant | Exon 8 of 33 | ENST00000320301.11 | NP_149045.3 | |
PCDH15 | NM_001384140.1 | c.875C>G | p.Pro292Arg | missense_variant, splice_region_variant | Exon 8 of 38 | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.875C>G | p.Pro292Arg | missense_variant, splice_region_variant | Exon 8 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.875C>G | p.Pro292Arg | missense_variant, splice_region_variant | Exon 8 of 38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251218 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460086Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726486 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 1F Uncertain:2
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. -
The p.Pro292Arg variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 24498627) and has been identified in 0.0009% (1/113578) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138744579). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 557886) and has been interpreted as a variant of uncertain significance by Counsyl and CeGaT Center for Human Genetics Tuebingen. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro292Arg variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015). -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at