10-54329622-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033056.4(PCDH15):c.679C>A(p.Arg227Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.679C>A	p.Arg227Ser	missense_variant	7/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.679C>A	p.Arg227Ser	missense_variant	7/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.679C>A	p.Arg227Ser	missense_variant	7/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.679C>A	p.Arg227Ser	missense_variant	7/38		NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449992 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;.;.;.;T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;.;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D;.;.;.;.;.;D;D;.;D;.;D;D;.;.;.;D;D;D;.;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;.;.;.;.;.;T;T;.;T;.;D;D;.;.;.;D;T;D;.;T;D;D
Sift4G	Uncertain	0.0070	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.83, 0.95, 0.91, 0.90, 0.45	.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;P;P;P;.;P;P;B
Vest4		0.78
MutPred		0.60		Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);.;Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);.;Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);.;Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);.;.;Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);.;.;Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);Gain of ubiquitination at K225 (P = 0.0561);
MVP		0.73
MPC		0.078
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.45
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs565693539; hg19: chr10-56089382;