rs200155519

Variant names:

• chr10-53806911-G-A
• rs200155519
• NM_001384140.1:c.4891C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001384140.1(PCDH15):​c.4891C>T​(p.Leu1631Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,613,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.435
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-53806911-G-A is Benign according to our data. Variant chr10-53806911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227837.
• BP7: Synonymous conserved (PhyloP=0.435 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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_001384140.1	MANE Select	c.4891C>T	p.Leu1631Leu	synonymous	Exon 38 of 38	NP_001371069.1
	PCDH15	NM_001354429.2		c.4825C>T	p.Leu1609Leu	synonymous	Exon 37 of 37	NP_001341358.1
	PCDH15	NM_001142771.2		c.4717C>T	p.Leu1573Leu	synonymous	Exon 36 of 36	NP_001136243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.4891C>T	p.Leu1631Leu	synonymous	Exon 38 of 38	ENSP00000495195.1
	PCDH15	ENST00000616114.4	TSL:1	c.4696C>T	p.Leu1566Leu	synonymous	Exon 34 of 34	ENSP00000483745.1
	PCDH15	ENST00000621708.4	TSL:5	c.4717C>T	p.Leu1573Leu	synonymous	Exon 36 of 36	ENSP00000484454.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000817 AC: 203 AN: 248606 AF XY: 0.000733

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000512 AC: 749 AN: 1461654 Hom.: 1 Cov.: 33 AF XY: 0.000481 AC XY: 350 AN XY: 727108

African (AFR) AF: 0.00206 AC: 69 AN: 33472

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 158 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000319 AC: 355 AN: 1111826

Other (OTH) AF: 0.00104 AC: 63 AN: 60372

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74430

African (AFR) AF: 0.00325 AC: 135 AN: 41542

American (AMR) AF: 0.00105 AC: 16 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.00146

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	PCDH15-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.41
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200155519; hg19: chr10-55566671;