NM_033056.4:c.1917+959C>A

Variant names:

• chr10-54131916-G-T
• rs9787578
• NM_033056.4:c.1917+959C>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.1917+959C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,008 control chromosomes in the GnomAD database, including 6,620 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 0.27 (6620 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+959C>A		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+959C>A		intron_variant	Intron 15 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1917+959C>A		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+959C>A		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40816 AN: 151890 Hom.: 6624 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.269

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

GnomAD4 genome AF: 0.269 AC: 40822 AN: 152008 Hom.: 6620 Cov.: 32 AF XY: 0.277 AC XY: 20568 AN XY: 74284

African (AFR) AF: 0.206 AC: 8535 AN: 41454

American (AMR) AF: 0.274 AC: 4184 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 804 AN: 3468

East Asian (EAS) AF: 0.875 AC: 4525 AN: 5170

South Asian (SAS) AF: 0.369 AC: 1778 AN: 4822

European-Finnish (FIN) AF: 0.276 AC: 2913 AN: 10570

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17213 AN: 67956

Other (OTH) AF: 0.272 AC: 572 AN: 2106

Alfa AF: 0.149 Hom.: 291

Bravo AF: 0.269

Asia WGS AF: 0.597 AC: 2070 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.080
DANN	Benign	0.46
PhyloP100		-1.1
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: rs9787578; hg19: chr10-55891676;