10-53823158-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Moderate BP6_Moderate

The NM_033056.4(PCDH15):c.4568G>A(p.Ser1523Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1523E?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-53823158-CT-CCTC is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.115240395).
• BP6: Variant 10-53823158-C-T is Benign according to our data. Variant chr10-53823158-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 517308.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.4568G>A	p.Ser1523Asn	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2928G>A		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.4568G>A	p.Ser1523Asn	missense_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2928G>A		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2017

p.Ser1523Asn in exon 33 of PCDH15: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, >5 mammals have a asparagine (Asn) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not sugg est a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.6
Dann	Benign	0.95
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.70	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.16	N;.;.;N;N;N;.;N;N
REVEL	Benign	0.073
Sift	Benign	0.039	D;.;.;D;D;D;.;D;D
Sift4G	Uncertain	0.043	D;D;D;D;D;D;D;D;D
Polyphen		0.0010	B;.;.;B;B;B;.;B;B
Vest4		0.029
MutPred		0.16		.;.;.;Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;.;
MVP		0.71
MPC		0.027
ClinPred		0.12	T
GERP RS		1.6
Varity_R		0.063
gMVP		0.32

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: rs1377421029; hg19: chr10-55582918;