rs1554827269

Variant names:

• chr10-53840441-A-G
• rs1554827269
• NM_033056.4:c.3862T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033056.4(PCDH15):​c.3862T>C​(p.Ser1288Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. S1288S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.99
• Publications: 1 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 29 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 29 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 29 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3862T>C	p.Ser1288Pro	missense_variant	Exon 29 of 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: no assertion criteria provided

Submissions by phenotype

Usher syndrome type 1F Uncertain:1

Sep 28, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T;.;.;.;.;T;.;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	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	Benign	0.058	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L
PhyloP100		5.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	.;.;.;.;.;.;.;.;.;D;.;N;N;.;D;.;.;N;N;N;.;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.026	.;.;.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
Sift4G	Uncertain	0.0030	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, 1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4		0.92
MutPred		0.50		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;Loss of sheet (P = 0.0181);.;.;.;Loss of sheet (P = 0.0181);.;.;.;.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;Loss of sheet (P = 0.0181);
MVP		0.84
MPC		0.19
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.78
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1554827269; hg19: chr10-55600201;