rs201816080

Variant names:

• chr10-53961877-G-A
• rs201816080
• NM_033056.4:c.2884C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-53961877-G-A
• chr10-53961877-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000644397.2(PCDH15):​c.2884C>T​(p.Arg962Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,608,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R962L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: PCDH15 ENST00000644397.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.812
• Publications: 17 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011024535).
• BP6: Variant 10-53961877-G-A is Benign according to our data. Variant chr10-53961877-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164914.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000473 (72/152182) while in subpopulation EAS AF = 0.0126 (65/5170). AF 95% confidence interval is 0.0101. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644397.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.2884C>T	p.Arg962Cys	missense	Exon 22 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2884C>T	p.Arg962Cys	missense	Exon 22 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.2899C>T	p.Arg967Cys	missense	Exon 23 of 35	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.2884C>T	p.Arg962Cys	missense	Exon 22 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.2884C>T	p.Arg962Cys	missense	Exon 22 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.2905C>T	p.Arg969Cys	missense	Exon 23 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000921 AC: 231 AN: 250888 AF XY: 0.000929

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000261 AC: 380 AN: 1456296 Hom.: 0 Cov.: 29 AF XY: 0.000276 AC XY: 200 AN XY: 724600

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.000112 AC: 5 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00757 AC: 299 AN: 39488

South Asian (SAS) AF: 0.000385 AC: 33 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107686

Other (OTH) AF: 0.000598 AC: 36 AN: 60208

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74398

African (AFR) AF: 0.0000481 AC: 2 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0126 AC: 65 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000384 Hom.: 2

Bravo AF: 0.000499

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.00347 AC: 12 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Usher syndrome type 1F (2)
-	-	1	not specified (1)
-	-	1	PCDH15-related disorder (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.70	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.81
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.019	D
Polyphen		0.98	D
Vest4		0.44
MVP		0.87
MPC		0.21
ClinPred		0.22	T
GERP RS		4.1
Varity_R		0.45
gMVP		0.55
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201816080; hg19: chr10-55721637; COSMIC: COSV57282864;