rs201855435

Variant names:

• chr10-53809510-T-C
• rs201855435
• ENST00000395445.6:c.4534A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001142769.3(PCDH15):​c.4555A>G​(p.Ile1519Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,609,970 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PCDH15 NM_001142769.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.101
• Publications: 0 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 Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041541457).
• BP6: Variant 10-53809510-T-C is Benign according to our data. Variant chr10-53809510-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44032.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00018 (262/1457656) while in subpopulation AMR AF = 0.00576 (253/43918). AF 95% confidence interval is 0.00518. There are 2 homozygotes in GnomAdExome4. There are 111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142769.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001384140.1	MANE Select	c.4671+1046A>G		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.4555A>G	p.Ile1519Val	missense	Exon 37 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.4534A>G	p.Ile1512Val	missense	Exon 35 of 35	NP_001341340.1	Q96QU1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000395445.6	TSL:1	c.4534A>G	p.Ile1512Val	missense	Exon 35 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000644397.2	MANE Select	c.4671+1046A>G		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4476+1046A>G		intron	N/A	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000937 AC: 229 AN: 244512 AF XY: 0.000784

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000180 AC: 262 AN: 1457656 Hom.: 2 Cov.: 33 AF XY: 0.000153 AC XY: 111 AN XY: 724866

African (AFR) AF: 0.0000302 AC: 1 AN: 33108

American (AMR) AF: 0.00576 AC: 253 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110836

Other (OTH) AF: 0.000116 AC: 7 AN: 60166

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74478

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00464 AC: 71 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000699

ExAC AF: 0.000607 AC: 73

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	PCDH15-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.10
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.11
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Vest4		0.10
MVP		0.27
ClinPred		0.018	T
GERP RS		-2.3
Mutation Taster		=93/7	polymorphism

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: rs201855435; hg19: chr10-55569270; COSMIC: COSV104688549;