rs397517469

Positions:

• chr10-54236861-G-A

Variant summary

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

The NM_001384140.1(PCDH15):​c.947C>T​(p.Pro316Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.63

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	Protein	UniProt
PCDH15	NM_033056.4	c.947C>T	p.Pro316Leu	missense_variant	9/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.947C>T	p.Pro316Leu	missense_variant	9/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.947C>T	p.Pro316Leu	missense_variant	9/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.947C>T	p.Pro316Leu	missense_variant	9/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 29, 2012

The Pro316Leu variant in PCDH15 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the P ro316Leu variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, additional data is needed to d etermine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.97, 1.0, 0.99, 0.95, 0.97, 0.99	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;P;D;.;D;P;D
Vest4		0.74
MutPred		0.31		Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);.;Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);.;Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);.;Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);.;.;.;Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);.;.;Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);
MVP		0.88
MPC		0.20
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.55

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: rs397517469; hg19: chr10-55996621;