10-53900064-C-T

Variant names:

• chr10-53900064-C-T
• rs16913796
• NM_033056.4:c.3501+3179G>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.3501+3179G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 152,142 control chromosomes in the GnomAD database, including 734 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 0.094 (734 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.662
• 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, 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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.3501+3179G>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3501+3179G>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.3516+3179G>A		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.3501+3179G>A		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3501+3179G>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3522+3179G>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14259 AN: 152024 Hom.: 734 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0785

Gnomad OTH AF: 0.0840

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

GnomAD4 genome AF: 0.0937 AC: 14255 AN: 152142 Hom.: 734 Cov.: 32 AF XY: 0.0935 AC XY: 6957 AN XY: 74378

African (AFR) AF: 0.133 AC: 5523 AN: 41504

American (AMR) AF: 0.0703 AC: 1075 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.101 AC: 524 AN: 5174

South Asian (SAS) AF: 0.0917 AC: 442 AN: 4818

European-Finnish (FIN) AF: 0.0706 AC: 747 AN: 10580

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0785 AC: 5336 AN: 67986

Other (OTH) AF: 0.0827 AC: 175 AN: 2116

Alfa AF: 0.0806 Hom.: 891

Bravo AF: 0.0932

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.81
PhyloP100		-0.66
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: rs16913796; hg19: chr10-55659824;