rs397517452
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384140.1(PCDH15):c.1998-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001384140.1 splice_acceptor, intron
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.1998-2A>G | splice_acceptor_variant, intron_variant | Intron 16 of 32 | ENST00000320301.11 | NP_149045.3 | ||
PCDH15 | NM_001384140.1 | c.1998-2A>G | splice_acceptor_variant, intron_variant | Intron 16 of 37 | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1998-2A>G | splice_acceptor_variant, intron_variant | Intron 16 of 32 | 1 | NM_033056.4 | ENSP00000322604.6 | |||
PCDH15 | ENST00000644397.2 | c.1998-2A>G | splice_acceptor_variant, intron_variant | Intron 16 of 37 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460982Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726860
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1
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Usher syndrome type 1F Pathogenic:1
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not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 16 of the PCDH15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 46449). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Rare genetic deafness Pathogenic:1
The 1998-2A>G variant (PCDH15) has not been reported in the literature nor previ ously identified by our laboratory. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered spl icing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at