NM_033056.4:c.2885G>A

Variant names:

• chr10-53961876-C-T
• rs45483395
• NM_033056.4:c.2885G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033056.4(PCDH15):​c.2885G>A​(p.Arg962His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,608,818 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R962C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.20
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00913021).
• BP6: Variant 10-53961876-C-T is Benign according to our data. Variant chr10-53961876-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46457.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00262 (399/152182) while in subpopulation AFR AF = 0.00754 (313/41530). AF 95% confidence interval is 0.00685. There are 2 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2885G>A	p.Arg962His	missense	Exon 22 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2885G>A	p.Arg962His	missense	Exon 22 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.2900G>A	p.Arg967His	missense	Exon 23 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.2885G>A	p.Arg962His	missense	Exon 22 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.2885G>A	p.Arg962His	missense	Exon 22 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.2906G>A	p.Arg969His	missense	Exon 23 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 396 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000925 AC: 232 AN: 250940 AF XY: 0.000907

Gnomad AFR exome AF: 0.00740

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000828

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00130 AC: 1894 AN: 1456636 Hom.: 2 Cov.: 29 AF XY: 0.00119 AC XY: 866 AN XY: 724774

African (AFR) AF: 0.00702 AC: 234 AN: 33340

American (AMR) AF: 0.000403 AC: 18 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85830

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53322

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5750

European-Non Finnish (NFE) AF: 0.00141 AC: 1561 AN: 1107924

Other (OTH) AF: 0.00120 AC: 72 AN: 60220

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74406

African (AFR) AF: 0.00754 AC: 313 AN: 41530

American (AMR) AF: 0.00118 AC: 18 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.0000259 Hom.: 3

Bravo AF: 0.00299

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000988 AC: 120

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	1	1	Usher syndrome type 1F (2)
-	-	1	PCDH15-related disorder (1)
-	1	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.038
Sift	Benign	0.061	T
Sift4G	Benign	0.14	T
Polyphen		0.0090	B
Vest4		0.23
MVP		0.58
MPC		0.033
ClinPred		0.0052	T
GERP RS		1.7
Varity_R		0.13
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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: rs45483395; hg19: chr10-55721636;