rs1935468

Variant names:

• chr10-54323965-T-C
• rs1935468
• NM_033056.4:c.705+5631A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033056.4(PCDH15):​c.705+5631A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 151,980 control chromosomes in the GnomAD database, including 38,583 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38583 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.82
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.705+5631A>G		intron_variant	Intron 7 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.705+5631A>G		intron_variant	Intron 7 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.705+5631A>G		intron_variant	Intron 7 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.705+5631A>G		intron_variant	Intron 7 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107131 AN: 151862 Hom.: 38543 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.730

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.706 AC: 107231 AN: 151980 Hom.: 38583 Cov.: 32 AF XY: 0.698 AC XY: 51825 AN XY: 74262

African (AFR) AF: 0.748 AC: 31027 AN: 41468

American (AMR) AF: 0.676 AC: 10296 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2662 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1154 AN: 5176

South Asian (SAS) AF: 0.582 AC: 2799 AN: 4810

European-Finnish (FIN) AF: 0.690 AC: 7279 AN: 10544

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49428 AN: 67976

Other (OTH) AF: 0.727 AC: 1536 AN: 2112

Alfa AF: 0.718 Hom.: 20121

Bravo AF: 0.707

Asia WGS AF: 0.441 AC: 1537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.050
DANN	Benign	0.78
PhyloP100		-2.8
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs1935468; hg19: chr10-56083725;