chr10-54304954-G-A

Variant names:

• chr10-54304954-G-A
• rs978841
• NM_033056.4:c.876+12317C>T

Variant summary

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

The NM_033056.4(PCDH15):​c.876+12317C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 151,660 control chromosomes in the GnomAD database, including 6,623 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 0.26 (6623 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.876+12317C>T		intron_variant	Intron 8 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.876+12317C>T		intron_variant	Intron 8 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.876+12317C>T		intron_variant	Intron 8 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.876+12317C>T		intron_variant	Intron 8 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40021 AN: 151540 Hom.: 6626 Cov.: 32

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.300

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

GnomAD4 genome AF: 0.264 AC: 40024 AN: 151660 Hom.: 6623 Cov.: 32 AF XY: 0.256 AC XY: 18961 AN XY: 74086

African (AFR) AF: 0.0975 AC: 4035 AN: 41384

American (AMR) AF: 0.239 AC: 3628 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1461 AN: 3470

East Asian (EAS) AF: 0.0511 AC: 264 AN: 5170

South Asian (SAS) AF: 0.138 AC: 662 AN: 4810

European-Finnish (FIN) AF: 0.273 AC: 2870 AN: 10502

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25889 AN: 67812

Other (OTH) AF: 0.297 AC: 627 AN: 2114

Alfa AF: 0.312 Hom.: 1077

Bravo AF: 0.254

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.73
DANN	Benign	0.48
PhyloP100		-0.13
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: rs978841; hg19: chr10-56064714;