rs2050545

Variant names:

• chr10-54743717-C-T
• rs2050545
• NM_033056.4:c.-29+57208G>A

Variant summary

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

The NM_033056.4(PCDH15):​c.-29+57208G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 151,884 control chromosomes in the GnomAD database, including 56,437 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 0.86 (56437 hom., cov: 30)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.767
• Publications: 3 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.-29+57208G>A		intron_variant	Intron 1 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.-29+57208G>A		intron_variant	Intron 1 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.-29+57208G>A		intron_variant	Intron 1 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.-29+57208G>A		intron_variant	Intron 1 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130053 AN: 151770 Hom.: 56415 Cov.: 30

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.863

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

GnomAD4 genome AF: 0.857 AC: 130116 AN: 151884 Hom.: 56437 Cov.: 30 AF XY: 0.850 AC XY: 63111 AN XY: 74248

African (AFR) AF: 0.818 AC: 33878 AN: 41426

American (AMR) AF: 0.731 AC: 11110 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3257 AN: 3472

East Asian (EAS) AF: 0.521 AC: 2680 AN: 5140

South Asian (SAS) AF: 0.781 AC: 3762 AN: 4814

European-Finnish (FIN) AF: 0.894 AC: 9444 AN: 10564

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.927 AC: 63013 AN: 67948

Other (OTH) AF: 0.861 AC: 1814 AN: 2106

Alfa AF: 0.899 Hom.: 153986

Bravo AF: 0.843

Asia WGS AF: 0.652 AC: 2267 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.9
DANN	Benign	0.42
PhyloP100		0.77
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: rs2050545; hg19: chr10-56503477;