10-54297661-T-C

Variant names:

• chr10-54297661-T-C
• rs7901045
• NM_033056.4:c.876+19610A>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.876+19610A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 152,030 control chromosomes in the GnomAD database, including 40,912 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 0.72 (40912 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.876+19610A>G		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.876+19610A>G		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.891+19610A>G		intron	N/A	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.876+19610A>G		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.876+19610A>G		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.876+19610A>G		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110072 AN: 151912 Hom.: 40856 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.750

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

GnomAD4 genome AF: 0.725 AC: 110187 AN: 152030 Hom.: 40912 Cov.: 31 AF XY: 0.715 AC XY: 53156 AN XY: 74310

African (AFR) AF: 0.820 AC: 34026 AN: 41482

American (AMR) AF: 0.690 AC: 10538 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2756 AN: 3468

East Asian (EAS) AF: 0.220 AC: 1133 AN: 5140

South Asian (SAS) AF: 0.573 AC: 2756 AN: 4810

European-Finnish (FIN) AF: 0.664 AC: 7016 AN: 10566

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49335 AN: 67972

Other (OTH) AF: 0.747 AC: 1574 AN: 2106

Alfa AF: 0.679 Hom.: 2489

Bravo AF: 0.731

Asia WGS AF: 0.439 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.31
PhyloP100		-1.5
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: rs7901045; hg19: chr10-56057421;