rs113363047

Variant names:

• chr10-53822122-CGTT-C
• rs113363047
• NM_033056.4:c.5601_5603delAAC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.5601_5603delAAC​(p.Thr1868del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,613,894 control chromosomes in the GnomAD database, including 347 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1867T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (175 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (172 hom.)
• Consequence: PCDH15 NM_033056.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:2 B:10 O:1
• Conservation: PhyloP100: 2.86
• Publications: 5 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_033056.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-53822122-CGTT-C is Benign according to our data. Variant chr10-53822122-CGTT-C is described in ClinVar as Benign. ClinVar VariationId is 46505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

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.5601_5603delAAC	p.Thr1868del	disruptive_inframe_deletion	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-1895_4368-1893delAAC		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.5622_5624delAAC	p.Thr1875del	disruptive_inframe_deletion	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.5601_5603delAAC	p.Thr1868del	disruptive_inframe_deletion	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.4368-1895_4368-1893delAAC		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4388+5268_4388+5270delAAC		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3918 AN: 151976 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0221

GnomAD2 exomes AF: 0.00720 AC: 1811 AN: 251400 AF XY: 0.00521

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00334 AC: 4877 AN: 1461800 Hom.: 172 AF XY: 0.00293 AC XY: 2134 AN XY: 727184

African (AFR) AF: 0.0913 AC: 3056 AN: 33474

American (AMR) AF: 0.00664 AC: 297 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26134

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.000673 AC: 58 AN: 86240

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53418

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000774 AC: 861 AN: 1111948

Other (OTH) AF: 0.00773 AC: 467 AN: 60396

GnomAD4 genome AF: 0.0259 AC: 3945 AN: 152094 Hom.: 175 Cov.: 32 AF XY: 0.0257 AC XY: 1909 AN XY: 74376

African (AFR) AF: 0.0869 AC: 3602 AN: 41444

American (AMR) AF: 0.0136 AC: 208 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

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

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68012

Other (OTH) AF: 0.0218 AC: 46 AN: 2106

Alfa AF: 0.0138 Hom.: 15

Bravo AF: 0.0301

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
1	-	1	Usher syndrome type 1F (2)
-	-	1	Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885: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		2.9
Mutation Taster		=85/15	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113363047;

hg19: chr10-55581882;

COSMIC: COSV100225657;