10-53995731-C-T

Variant names:

• chr10-53995731-C-T
• rs2135720
• NM_033056.4:c.2786G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.2786G>A​(p.Arg929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,478 control chromosomes in the GnomAD database, including 44,202 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R929G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4506 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39696 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.850
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.7762146E-5).
• BP6: Variant 10-53995731-C-T is Benign according to our data. Variant chr10-53995731-C-T is described in ClinVar as Benign. ClinVar VariationId is 46456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

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.2786G>A	p.Arg929Gln	missense	Exon 21 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2786G>A	p.Arg929Gln	missense	Exon 21 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.2801G>A	p.Arg934Gln	missense	Exon 22 of 35	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.2786G>A	p.Arg929Gln	missense	Exon 21 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.2786G>A	p.Arg929Gln	missense	Exon 21 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.2807G>A	p.Arg936Gln	missense	Exon 22 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35400 AN: 151858 Hom.: 4509 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.252 AC: 63196 AN: 250772 AF XY: 0.259

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.221 AC: 322360 AN: 1461502 Hom.: 39696 Cov.: 33 AF XY: 0.226 AC XY: 164513 AN XY: 727052

African (AFR) AF: 0.242 AC: 8094 AN: 33468

American (AMR) AF: 0.203 AC: 9068 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4634 AN: 26126

East Asian (EAS) AF: 0.511 AC: 20281 AN: 39680

South Asian (SAS) AF: 0.411 AC: 35469 AN: 86242

European-Finnish (FIN) AF: 0.235 AC: 12569 AN: 53384

Middle Eastern (MID) AF: 0.168 AC: 970 AN: 5764

European-Non Finnish (NFE) AF: 0.196 AC: 217529 AN: 1111746

Other (OTH) AF: 0.228 AC: 13746 AN: 60386

GnomAD4 genome AF: 0.233 AC: 35422 AN: 151976 Hom.: 4506 Cov.: 32 AF XY: 0.239 AC XY: 17760 AN XY: 74290

African (AFR) AF: 0.241 AC: 10007 AN: 41456

American (AMR) AF: 0.210 AC: 3202 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 640 AN: 3470

East Asian (EAS) AF: 0.505 AC: 2613 AN: 5172

South Asian (SAS) AF: 0.420 AC: 2024 AN: 4814

European-Finnish (FIN) AF: 0.233 AC: 2460 AN: 10558

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13704 AN: 67938

Other (OTH) AF: 0.215 AC: 454 AN: 2108

Alfa AF: 0.212 Hom.: 16023

Bravo AF: 0.226

TwinsUK AF: 0.187 AC: 695

ALSPAC AF: 0.201 AC: 775

ESP6500AA AF: 0.233 AC: 1027

ESP6500EA AF: 0.200 AC: 1719

ExAC AF: 0.256 AC: 31094

Asia WGS AF: 0.424 AC: 1475 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.187

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.094	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.000098	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.85
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.016
Sift	Benign	0.38	T
Sift4G	Benign	0.15	T
Polyphen		0.010	B
Vest4		0.10
MPC		0.032
ClinPred		0.00056	T
GERP RS		3.0
Varity_R		0.066
gMVP		0.30
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2135720; hg19: chr10-55755491; COSMIC: COSV57264676;