rs397517451

Variant names:

• chr10-54664246-TA-T
• rs397517451
• NM_033056.4:c.16delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001384140.1(PCDH15):​c.16delT​(p.Tyr6IlefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.56
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 287 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-54664246-TA-T is Pathogenic according to our data. Variant chr10-54664246-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 46446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 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.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.16delT	p.Tyr6IlefsTer6	frameshift	Exon 2 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459528 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726078

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110570

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Rare genetic deafness (1)
1	-	-	Usher syndrome type 1F (1)
1	-	-	USHER SYNDROME, TYPE ID/F, DIGENIC (1)
-	-	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs397517451; hg19: chr10-56424006;