chr10-54444531-G-T

Variant names:

• chr10-54444531-G-T
• rs7476422
• NM_033056.4:c.158-65589C>A

Variant summary

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

The NM_001142763.2(PCDH15):​c.173-65589C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 151,522 control chromosomes in the GnomAD database, including 40,414 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 0.72 (40414 hom., cov: 32)
• Consequence: PCDH15 NM_001142763.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 6 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

ENSG00000294506 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142763.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.158-65589C>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.158-65589C>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.173-65589C>A		intron	N/A	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.158-65589C>A		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.158-65589C>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.158-65589C>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.719 AC: 108874 AN: 151404 Hom.: 40372 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.744

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

GnomAD4 genome AF: 0.719 AC: 108966 AN: 151522 Hom.: 40414 Cov.: 32 AF XY: 0.708 AC XY: 52425 AN XY: 74040

African (AFR) AF: 0.809 AC: 33491 AN: 41414

American (AMR) AF: 0.609 AC: 9224 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2961 AN: 3462

East Asian (EAS) AF: 0.184 AC: 946 AN: 5134

South Asian (SAS) AF: 0.541 AC: 2610 AN: 4822

European-Finnish (FIN) AF: 0.675 AC: 7129 AN: 10568

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 49998 AN: 67672

Other (OTH) AF: 0.738 AC: 1549 AN: 2100

Alfa AF: 0.725 Hom.: 176412

Bravo AF: 0.719

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.36
PhyloP100		0.74
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: rs7476422; hg19: chr10-56204291;