10-53822876-T-C

Variant names:

• chr10-53822876-T-C
• rs111033362
• NM_033056.4:c.4850A>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_033056.4(PCDH15):​c.4850A>G​(p.Asn1617Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,112 control chromosomes in the GnomAD database, including 81 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1617D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (72 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0200
• 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, 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=0.0058371127).
• BP6: Variant 10-53822876-T-C is Benign according to our data. Variant chr10-53822876-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00611 (931/152304) while in subpopulation NFE AF = 0.00966 (657/68008). AF 95% confidence interval is 0.00905. There are 9 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4850A>G	p.Asn1617Ser	missense	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2646A>G		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.4871A>G	p.Asn1624Ser	missense	Exon 35 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.4850A>G	p.Asn1617Ser	missense	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2646A>G		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.4388+4517A>G		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 931 AN: 152186 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00966

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00541 AC: 1361 AN: 251424 AF XY: 0.00538

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00897

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00920 AC: 13454 AN: 1461808 Hom.: 72 Cov.: 33 AF XY: 0.00898 AC XY: 6531 AN XY: 727202

African (AFR) AF: 0.00164 AC: 55 AN: 33474

American (AMR) AF: 0.00429 AC: 192 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86258

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0111 AC: 12375 AN: 1111946

Other (OTH) AF: 0.00839 AC: 507 AN: 60394

GnomAD4 genome AF: 0.00611 AC: 931 AN: 152304 Hom.: 9 Cov.: 32 AF XY: 0.00564 AC XY: 420 AN XY: 74472

African (AFR) AF: 0.00274 AC: 114 AN: 41576

American (AMR) AF: 0.00732 AC: 112 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00966 AC: 657 AN: 68008

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00774 Hom.: 23

Bravo AF: 0.00630

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00526 AC: 638

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00949

EpiControl AF: 0.00907

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Usher syndrome type 1F (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.47
DANN	Benign	0.24
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		0.020
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.046
Sift	Benign	0.52	T
Sift4G	Benign	0.76	T
Polyphen		0.0010	B
Vest4		0.018
MVP		0.37
MPC		0.025
ClinPred		0.0019	T
GERP RS		0.18
Varity_R		0.020
gMVP		0.062
Mutation Taster		=100/0	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: rs111033362; hg19: chr10-55582636; COSMIC: COSV100214893;