10-53827547-G-C

Position:

• chr10-53827547-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033056.4(PCDH15):​c.4213C>G​(p.Arg1405Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_033056.4 missense, splice_region
• Scores: Splicing: ADA: 0.9884
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.4213C>G	p.Arg1405Gly	missense_variant, splice_region_variant	32/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4213C>G	p.Arg1405Gly	missense_variant, splice_region_variant	32/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4213C>G	p.Arg1405Gly	missense_variant, splice_region_variant	32/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.4213C>G	p.Arg1405Gly	missense_variant, splice_region_variant	32/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249056 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Aug 03, 2017

The p.Arg1405Gly variant in PCDH15 has not been previously reported in individua ls with hearing loss or Usher syndrome, but has been identified in 1/17246 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org/; dbSNP rs148046721). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic ro le. Computational prediction tools and conservation analyses suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg14 05Gly variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.;.;.;.;T;.;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	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
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D;D;.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;.;D;D
Vest4		0.88
MutPred		0.74		Loss of MoRF binding (P = 0.0379);Loss of MoRF binding (P = 0.0379);.;.;Loss of MoRF binding (P = 0.0379);.;.;Loss of MoRF binding (P = 0.0379);.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0379);.;.;.;.;Loss of MoRF binding (P = 0.0379);
MVP		0.83
MPC		0.24
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.19
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs148046721; hg19: chr10-55587307;