rs192813057

Variant names:

• chr10-54023128-G-A
• rs192813057
• NM_033056.4:c.2290C>T
• PCDH15 p.Arg764Cys

Your query was ambiguous. Multiple possible variants found:

• chr10-54023128-G-A
• chr10-54023128-G-C
• chr10-54023128-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001384140.1(PCDH15):​c.2290C>T​(p.Arg764Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,613,762 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R764H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 1.56
• Publications: 9 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 Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.120475024).

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_033056.4	MANE Plus Clinical	c.2290C>T	p.Arg764Cys	missense	Exon 19 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2290C>T	p.Arg764Cys	missense	Exon 19 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.2305C>T	p.Arg769Cys	missense	Exon 20 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.2290C>T	p.Arg764Cys	missense	Exon 19 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.2290C>T	p.Arg764Cys	missense	Exon 19 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.2311C>T	p.Arg771Cys	missense	Exon 20 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000367 AC: 92 AN: 250880 AF XY: 0.000361

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000626

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000692 AC: 1012 AN: 1461640 Hom.: 1 Cov.: 31 AF XY: 0.000671 AC XY: 488 AN XY: 727110

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000837 AC: 931 AN: 1111862

Other (OTH) AF: 0.000861 AC: 52 AN: 60384

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74334

African (AFR) AF: 0.000385 AC: 16 AN: 41526

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000546 Hom.: 1

Bravo AF: 0.000336

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	not specified (2)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F (1)
-	1	-	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.025	D
Varity_R		0.21
gMVP		0.53
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs192813057;

hg19: chr10-55782888;

COSMIC: COSV57279849;