rs142016527

Variant names:

• chr10-54664267-T-C
• rs142016527
• NM_033056.4:c.-5A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):​c.-5A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000996 in 1,607,968 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: PCDH15 NM_033056.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.44
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-54664267-T-C is Benign according to our data. Variant chr10-54664267-T-C is described in ClinVar as Benign. ClinVar VariationId is 178523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00532 (809/152164) while in subpopulation AFR AF = 0.0177 (737/41572). AF 95% confidence interval is 0.0167. There are 8 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.-5A>G		5_prime_UTR	Exon 2 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.-5A>G		5_prime_UTR	Exon 2 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.-5A>G		5_prime_UTR	Exon 2 of 35	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.-5A>G		5_prime_UTR	Exon 2 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.-5A>G		5_prime_UTR	Exon 2 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.-5A>G		5_prime_UTR	Exon 2 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152046 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00138 AC: 341 AN: 247202 AF XY: 0.000980

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000544 AC: 792 AN: 1455804 Hom.: 7 Cov.: 29 AF XY: 0.000450 AC XY: 326 AN XY: 724294

African (AFR) AF: 0.0191 AC: 635 AN: 33266

American (AMR) AF: 0.00131 AC: 58 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1107620

Other (OTH) AF: 0.00118 AC: 71 AN: 60122

GnomAD4 genome AF: 0.00532 AC: 809 AN: 152164 Hom.: 8 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74406

African (AFR) AF: 0.0177 AC: 737 AN: 41572

American (AMR) AF: 0.00347 AC: 53 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67934

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00246 Hom.: 0

Bravo AF: 0.00636

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (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	-0.41
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		1.4
Mutation Taster		=289/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142016527; hg19: chr10-56424027;