10-54560092-G-T

Variant names:

• chr10-54560092-G-T
• rs1937389
• NM_033056.4:c.92-32215C>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.92-32215C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 151,856 control chromosomes in the GnomAD database, including 46,808 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 0.78 (46808 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.722
• 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

ENSG00000234173 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.92-32215C>A		intron_variant	Intron 2 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.92-32215C>A		intron_variant	Intron 2 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.92-32215C>A		intron_variant	Intron 2 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.92-32215C>A		intron_variant	Intron 2 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.777 AC: 117886 AN: 151738 Hom.: 46784 Cov.: 31

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.853

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.774

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

GnomAD4 genome AF: 0.777 AC: 117961 AN: 151856 Hom.: 46808 Cov.: 31 AF XY: 0.779 AC XY: 57808 AN XY: 74184

African (AFR) AF: 0.602 AC: 24924 AN: 41420

American (AMR) AF: 0.828 AC: 12622 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2408 AN: 3462

East Asian (EAS) AF: 0.991 AC: 5112 AN: 5158

South Asian (SAS) AF: 0.888 AC: 4273 AN: 4814

European-Finnish (FIN) AF: 0.853 AC: 9030 AN: 10588

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57043 AN: 67856

Other (OTH) AF: 0.777 AC: 1637 AN: 2108

Alfa AF: 0.814 Hom.: 156968

Bravo AF: 0.766

Asia WGS AF: 0.912 AC: 3169 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.48
DANN	Benign	0.56
PhyloP100		-0.72
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: rs1937389; hg19: chr10-56319852;