10-53822914-C-A

Variant names:

• chr10-53822914-C-A
• rs148718874
• NM_033056.4:c.4812G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):​c.4812G>T​(p.Arg1604Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000638 in 1,614,108 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1604G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (15 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -0.264
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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=0.0037893355).
• BP6: Variant 10-53822914-C-A is Benign according to our data. Variant chr10-53822914-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000867 (132/152264) while in subpopulation EAS AF = 0.0234 (121/5172). AF 95% confidence interval is 0.02. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.4812G>T	p.Arg1604Ser	missense	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2684G>T		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.4833G>T	p.Arg1611Ser	missense	Exon 35 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.4812G>T	p.Arg1604Ser	missense	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2684G>T		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4388+4479G>T		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00210 AC: 529 AN: 251356 AF XY: 0.00186

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000614 AC: 897 AN: 1461844 Hom.: 15 Cov.: 33 AF XY: 0.000568 AC XY: 413 AN XY: 727220

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0206 AC: 816 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111980

Other (OTH) AF: 0.00106 AC: 64 AN: 60396

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74452

African (AFR) AF: 0.000144 AC: 6 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15282

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

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000979 Hom.: 4

Bravo AF: 0.00129

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	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	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.8
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.081	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.26
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.13
Sift	Benign	0.088	T
Sift4G	Benign	0.56	T
Polyphen		0.13	B
Vest4		0.38
MutPred		0.45		Loss of MoRF binding (P = 0.0731)
MVP		0.47
MPC		0.032
ClinPred		0.0051	T
GERP RS		-1.9
Varity_R		0.082
gMVP		0.24
Mutation Taster		=98/2	polymorphism

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: rs148718874; hg19: chr10-55582674; COSMIC: COSV100214895;