NM_033056.4:c.3502-8C>T

Variant names:

• chr10-53866865-G-A
• rs184144118
• NM_033056.4:c.3502-8C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033056.4(PCDH15):​c.3502-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,557,730 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: PCDH15 NM_033056.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003810
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.109
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-53866865-G-A is Benign according to our data. Variant chr10-53866865-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46469.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00407 (558/136958) while in subpopulation NFE AF = 0.00538 (355/65964). AF 95% confidence interval is 0.00492. There are 1 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

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.3502-8C>T		splice_region intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3502-8C>T		splice_region intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.3517-8C>T		splice_region 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.3502-8C>T		splice_region intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3502-8C>T		splice_region intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3523-8C>T		splice_region intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 558 AN: 136852 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00859

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.00538

Gnomad OTH AF: 0.0111

GnomAD2 exomes AF: 0.00443 AC: 1069 AN: 241144 AF XY: 0.00432

Gnomad AFR exome AF: 0.000771

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.00819

Gnomad EAS exome AF: 0.0000649

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00614

Gnomad OTH exome AF: 0.00765

GnomAD4 exome AF: 0.00544 AC: 7734 AN: 1420772 Hom.: 34 Cov.: 26 AF XY: 0.00532 AC XY: 3774 AN XY: 709346

African (AFR) AF: 0.00133 AC: 43 AN: 32384

American (AMR) AF: 0.00541 AC: 238 AN: 44000

Ashkenazi Jewish (ASJ) AF: 0.00729 AC: 188 AN: 25794

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39432

South Asian (SAS) AF: 0.00144 AC: 123 AN: 85162

European-Finnish (FIN) AF: 0.00222 AC: 118 AN: 53262

Middle Eastern (MID) AF: 0.0127 AC: 72 AN: 5676

European-Non Finnish (NFE) AF: 0.00610 AC: 6569 AN: 1076138

Other (OTH) AF: 0.00648 AC: 382 AN: 58924

GnomAD4 genome AF: 0.00407 AC: 558 AN: 136958 Hom.: 1 Cov.: 31 AF XY: 0.00365 AC XY: 242 AN XY: 66348

African (AFR) AF: 0.00162 AC: 57 AN: 35084

American (AMR) AF: 0.00524 AC: 71 AN: 13538

Ashkenazi Jewish (ASJ) AF: 0.00859 AC: 29 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 2148

South Asian (SAS) AF: 0.00124 AC: 5 AN: 4018

European-Finnish (FIN) AF: 0.00164 AC: 16 AN: 9772

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.00538 AC: 355 AN: 65964

Other (OTH) AF: 0.0109 AC: 21 AN: 1918

Alfa AF: 0.00434 Hom.: 2

Bravo AF: 0.00447

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	PCDH15-related disorder (1)
-	1	-	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.21
DANN	Benign	0.31
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
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: rs184144118; hg19: chr10-55626625;