10-54668517-C-T

Variant names:

• chr10-54668517-C-T
• rs7902184
• NM_033056.4:c.-28-4227G>A

Variant summary

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

The NM_001384140.1(PCDH15):​c.-28-4227G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 151,930 control chromosomes in the GnomAD database, including 10,614 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 0.36 (10614 hom., cov: 32)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298
• 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 Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.-28-4227G>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.-28-4227G>A		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.-28-4227G>A		intron	N/A	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.-28-4227G>A		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.-28-4227G>A		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.-28-4227G>A		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55148 AN: 151812 Hom.: 10591 Cov.: 32

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.363 AC: 55219 AN: 151930 Hom.: 10614 Cov.: 32 AF XY: 0.358 AC XY: 26544 AN XY: 74238

African (AFR) AF: 0.496 AC: 20551 AN: 41426

American (AMR) AF: 0.326 AC: 4970 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1416 AN: 3470

East Asian (EAS) AF: 0.213 AC: 1101 AN: 5164

South Asian (SAS) AF: 0.289 AC: 1397 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2612 AN: 10562

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 21993 AN: 67926

Other (OTH) AF: 0.377 AC: 797 AN: 2112

Alfa AF: 0.337 Hom.: 37635

Bravo AF: 0.382

Asia WGS AF: 0.277 AC: 966 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	8.9
DANN	Benign	0.71
PhyloP100		-0.30
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: rs7902184; hg19: chr10-56428277;