rs61735473

Variant names:

• chr10-54185214-C-T
• rs61735473
• NM_033056.4:c.1360G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-54185214-C-T
• chr10-54185214-C-A
• chr10-54185214-C-G

Variant summary

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

The NM_001384140.1(PCDH15):​c.1360G>A​(p.Val454Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,613,434 control chromosomes in the GnomAD database, including 42 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V454V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.36
• Publications: 11 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=0.003993243).
• BP6: Variant 10-54185214-C-T is Benign according to our data. Variant chr10-54185214-C-T is described in ClinVar as Benign. ClinVar VariationId is 46442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00943 (1434/152050) while in subpopulation AFR AF = 0.032 (1326/41464). AF 95% confidence interval is 0.0305. There are 24 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.1360G>A	p.Val454Ile	missense	Exon 12 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 12 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1375G>A	p.Val459Ile	missense	Exon 13 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.1360G>A	p.Val454Ile	missense	Exon 12 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1360G>A	p.Val454Ile	missense	Exon 12 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1381G>A	p.Val461Ile	missense	Exon 13 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00936 AC: 1422 AN: 151934 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00282 AC: 709 AN: 251354 AF XY: 0.00214

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00109 AC: 1600 AN: 1461384 Hom.: 18 Cov.: 31 AF XY: 0.00103 AC XY: 752 AN XY: 727010

African (AFR) AF: 0.0335 AC: 1121 AN: 33458

American (AMR) AF: 0.00212 AC: 95 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111632

Other (OTH) AF: 0.00260 AC: 157 AN: 60382

GnomAD4 genome AF: 0.00943 AC: 1434 AN: 152050 Hom.: 24 Cov.: 32 AF XY: 0.00896 AC XY: 666 AN XY: 74326

African (AFR) AF: 0.0320 AC: 1326 AN: 41464

American (AMR) AF: 0.00400 AC: 61 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67974

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00418 Hom.: 25

Bravo AF: 0.0110

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.019
Sift	Benign	0.52	T
Sift4G	Benign	0.069	T
Polyphen		0.033	B
Vest4		0.17
MVP		0.27
MPC		0.029
ClinPred		0.0086	T
GERP RS		2.5
Varity_R		0.071
gMVP		0.16
Mutation Taster		=96/4	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: rs61735473; hg19: chr10-55944974; COSMIC: COSV57313529;