chr10-54799959-T-C

Variant names:

• chr10-54799959-T-C
• rs10509019
• NM_033056.4:c.-29+966A>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.-29+966A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0976 in 152,132 control chromosomes in the GnomAD database, including 971 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 0.098 (971 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 0 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.-29+966A>G		intron_variant	Intron 1 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.-29+966A>G		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+966A>G		intron_variant	Intron 1 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.-29+966A>G		intron_variant	Intron 1 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 14835 AN: 152014 Hom.: 970 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0896

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.0883

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

GnomAD4 genome AF: 0.0976 AC: 14841 AN: 152132 Hom.: 971 Cov.: 32 AF XY: 0.0984 AC XY: 7317 AN XY: 74366

African (AFR) AF: 0.0251 AC: 1042 AN: 41562

American (AMR) AF: 0.0897 AC: 1371 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0459 AC: 157 AN: 3424

East Asian (EAS) AF: 0.223 AC: 1149 AN: 5156

South Asian (SAS) AF: 0.108 AC: 519 AN: 4822

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10592

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8756 AN: 67978

Other (OTH) AF: 0.0917 AC: 194 AN: 2116

Alfa AF: 0.111 Hom.: 139

Bravo AF: 0.0884

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.087
DANN	Benign	0.71
PhyloP100		-1.8
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: rs10509019; hg19: chr10-56559719;