10-53866870-GAA-GAAAA

Variant names:

• chr10-53866870-G-GAA
• rs5785023
• NM_033056.4:c.3502-15_3502-14dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_033056.4(PCDH15):​c.3502-15_3502-14dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,480,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.936
• 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, 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 10-53866870-G-GAA is Benign according to our data. Variant chr10-53866870-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 1164363.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3502-15_3502-14dupTT		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3502-15_3502-14dupTT		intron_variant	Intron 26 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-14_3502-13insTT		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3502-14_3502-13insTT		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0000734 AC: 11 AN: 149952 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000891

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000905 AC: 21 AN: 232130 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000504

Gnomad FIN exome AF: 0.0000497

Gnomad NFE exome AF: 0.0000942

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000201 AC: 268 AN: 1330104 Hom.: 0 Cov.: 23 AF XY: 0.000180 AC XY: 120 AN XY: 667968

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

African (AFR) AF: 0.000443 AC: 13 AN: 29370

American (AMR) AF: 0.0000712 AC: 3 AN: 42106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24952

East Asian (EAS) AF: 0.000795 AC: 27 AN: 33954

South Asian (SAS) AF: 0.000197 AC: 16 AN: 81248

European-Finnish (FIN) AF: 0.000115 AC: 6 AN: 52288

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5428

European-Non Finnish (NFE) AF: 0.000189 AC: 190 AN: 1005298

Other (OTH) AF: 0.000216 AC: 12 AN: 55460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000733 AC: 11 AN: 150054 Hom.: 0 Cov.: 22 AF XY: 0.0000547 AC XY: 4 AN XY: 73118

African (AFR) AF: 0.0000488 AC: 2 AN: 41006

American (AMR) AF: 0.0000663 AC: 1 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.0000998 AC: 1 AN: 10024

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

European-Non Finnish (NFE) AF: 0.0000891 AC: 6 AN: 67366

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000531 Hom.: 212

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs5785023; hg19: chr10-55626630;