rs753690225

Variant names:

• chr10-53822352-GAGGAAGAGGA-G
• rs753690225
• NM_033056.4:c.5364_5373delTCCTCTTCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_033056.4(PCDH15):​c.5364_5373delTCCTCTTCCT​(p.Pro1789LeufsTer52) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000127 in 1,579,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PCDH15 NM_033056.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 3.66
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. 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_033056.4	MANE Plus Clinical	c.5364_5373delTCCTCTTCCT	p.Pro1789LeufsTer52	frameshift	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2132_4368-2123delTCCTCTTCCT		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.5385_5394delTCCTCTTCCT	p.Pro1796LeufsTer52	frameshift	Exon 35 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5364_5373delTCCTCTTCCT	p.Pro1789LeufsTer52	frameshift	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2132_4368-2123delTCCTCTTCCT		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4388+5031_4388+5040delTCCTCTTCCT		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151620 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000314 AC: 6 AN: 191288 AF XY: 0.0000486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.000385

GnomAD4 exome AF: 0.0000133 AC: 19 AN: 1427796 Hom.: 0 AF XY: 0.0000113 AC XY: 8 AN XY: 707588

African (AFR) AF: 0.0000309 AC: 1 AN: 32356

American (AMR) AF: 0.00 AC: 0 AN: 38692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 37468

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51724

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1093468

Other (OTH) AF: 0.00 AC: 0 AN: 59172

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151620 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41260

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	not provided (2)
1	-	-	Retinal dystrophy (1)
-	1	-	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=0/200	disease causing

Splicing

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

Other links and lift over

dbSNP: rs753690225; hg19: chr10-55582112;