rs115559383

Variant names:

• chr10-53811585-T-C
• rs115559383
• NM_001384140.1:c.4526A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-53811585-T-C
• chr10-53811585-T-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001384140.1(PCDH15):​c.4526A>G​(p.Gln1509Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,572,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 7.62
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021119595).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001384140.1	MANE Select	c.4526A>G	p.Gln1509Arg	missense	Exon 36 of 38	NP_001371069.1
	PCDH15	NM_001354429.2		c.4460A>G	p.Gln1487Arg	missense	Exon 35 of 37	NP_001341358.1
	PCDH15	NM_001142770.3		c.4408A>G	p.Arg1470Gly	missense	Exon 34 of 36	NP_001136242.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.4526A>G	p.Gln1509Arg	missense	Exon 36 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.4389-921A>G		intron	N/A	ENSP00000378832.2
	PCDH15	ENST00000616114.4	TSL:1	c.4368-921A>G		intron	N/A	ENSP00000483745.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000133 AC: 30 AN: 225468 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 68 AN: 1420074 Hom.: 0 Cov.: 28 AF XY: 0.0000440 AC XY: 31 AN XY: 704662

African (AFR) AF: 0.00181 AC: 58 AN: 32068

American (AMR) AF: 0.000145 AC: 6 AN: 41332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 37890

South Asian (SAS) AF: 0.00 AC: 0 AN: 76682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1091314

Other (OTH) AF: 0.0000171 AC: 1 AN: 58482

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000617 AC XY: 46 AN XY: 74496

African (AFR) AF: 0.00200 AC: 83 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000942 Hom.: 0

Bravo AF: 0.000620

ESP6500AA AF: 0.00191 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000183 AC: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.021	T
PhyloP100		7.6
Sift4G	Uncertain	0.013	D
Vest4		0.84
MVP		0.66
ClinPred		0.071	T
GERP RS		5.3
Mutation Taster		=49/51	disease causing

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: rs115559383; hg19: chr10-55571345;