10-54020215-C-A
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_033056.4(PCDH15):c.2728G>T(p.Ala910Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A910T) has been classified as Uncertain significance.
Frequency
Consequence
NM_033056.4 missense
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: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.2728G>T | p.Ala910Ser | missense_variant | Exon 20 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.2728G>T | p.Ala910Ser | missense_variant | Exon 20 of 38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.000270 AC: 41AN: 151984Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000917 AC: 23AN: 250804 AF XY: 0.0000738 show subpopulations
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461482Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727032 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000283 AC: 43AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74354 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:2
PCDH15: BS1:Supporting -
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Ala910Ser var iant in PCDH15 has been reported in three individuals from Saudi Arabia with hea ring loss (Dallol 2016), and it has also been reported in ClinVar (Variation ID: 550483). This variant has also been identified in 0.12% (29/24020) African chro mosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction t ools and conservation analysis do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the p.Ala91 0Ser variant is uncertain, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting. -
PCDH15-related disorder Uncertain:1
The PCDH15 c.2728G>T variant is predicted to result in the amino acid substitution p.Ala910Ser. This variant has been reported in three unrelated patients with hearing loss, although conclusive evidence of pathogenicity was not presented (described as p.Ala915Ser, Dallol et al. 2016. PubMed ID: 27766948). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Usher syndrome type 1F Uncertain:1
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Optic atrophy Uncertain:1
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Usher syndrome type 1D Uncertain:1
NM_033056.3(PCDH15):c.2728G>T(A910S) is a missense variant classified as a variant of uncertain significance in the context of PCDH15-related disorders. A910S has been observed in cases with relevant disease (PMID: 27766948). Functional assessments of this variant are not available in the literature. A910S has been observed in population frequency databases (gnomAD: AFR 0.11%). In summary, there is insufficient evidence to classify NM_033056.3(PCDH15):c.2728G>T(A910S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at