10-54062675-T-C

Variant names:

• chr10-54062675-T-C
• rs7079133
• NM_033056.4:c.2220+4082A>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.2220+4082A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 151,364 control chromosomes in the GnomAD database, including 12,408 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 0.40 (12408 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.381
• Publications: 1 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2220+4082A>G		intron_variant	Intron 18 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2220+4082A>G		intron_variant	Intron 18 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2220+4082A>G		intron_variant	Intron 18 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2220+4082A>G		intron_variant	Intron 18 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60104 AN: 151246 Hom.: 12404 Cov.: 31

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.440

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

GnomAD4 genome AF: 0.397 AC: 60133 AN: 151364 Hom.: 12408 Cov.: 31 AF XY: 0.395 AC XY: 29162 AN XY: 73896

African (AFR) AF: 0.328 AC: 13535 AN: 41218

American (AMR) AF: 0.420 AC: 6385 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1904 AN: 3464

East Asian (EAS) AF: 0.158 AC: 807 AN: 5122

South Asian (SAS) AF: 0.284 AC: 1364 AN: 4798

European-Finnish (FIN) AF: 0.425 AC: 4418 AN: 10402

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.445 AC: 30196 AN: 67840

Other (OTH) AF: 0.437 AC: 922 AN: 2108

Alfa AF: 0.430 Hom.: 6847

Bravo AF: 0.398

Asia WGS AF: 0.241 AC: 836 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		0.38
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: rs7079133; hg19: chr10-55822435;