rs61862390

Variant names:

• chr10-53822367-G-A
• rs61862390
• NM_033056.4:c.5359C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-53822367-G-A
• chr10-53822367-G-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.5359C>T​(p.Pro1787Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,576,182 control chromosomes in the GnomAD database, including 344 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (37 hom., cov: 32)
  • Exomes 𝑓: 0.016 (307 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.06
• 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=0.0032382607).
• BP6: Variant 10-53822367-G-A is Benign according to our data. Variant chr10-53822367-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0152 (2304/151458) while in subpopulation AMR AF = 0.0216 (327/15138). AF 95% confidence interval is 0.0197. There are 37 homozygotes in GnomAd4. There are 1334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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.5359C>T	p.Pro1787Ser	missense	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2137C>T		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.5380C>T	p.Pro1794Ser	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.5359C>T	p.Pro1787Ser	missense	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2137C>T		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4388+5026C>T		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 151340 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00585

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00673

GnomAD2 exomes AF: 0.0184 AC: 3421 AN: 186126 AF XY: 0.0173

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00297

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0727

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0155 AC: 22153 AN: 1424724 Hom.: 307 Cov.: 32 AF XY: 0.0153 AC XY: 10770 AN XY: 705728

African (AFR) AF: 0.00214 AC: 69 AN: 32246

American (AMR) AF: 0.0202 AC: 773 AN: 38314

Ashkenazi Jewish (ASJ) AF: 0.00331 AC: 85 AN: 25702

East Asian (EAS) AF: 0.0000806 AC: 3 AN: 37204

South Asian (SAS) AF: 0.00838 AC: 697 AN: 83194

European-Finnish (FIN) AF: 0.0688 AC: 3537 AN: 51418

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5666

European-Non Finnish (NFE) AF: 0.0149 AC: 16234 AN: 1091948

Other (OTH) AF: 0.0127 AC: 749 AN: 59032

GnomAD4 genome AF: 0.0152 AC: 2304 AN: 151458 Hom.: 37 Cov.: 32 AF XY: 0.0180 AC XY: 1334 AN XY: 73970

African (AFR) AF: 0.00249 AC: 103 AN: 41304

American (AMR) AF: 0.0216 AC: 327 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3464

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5116

South Asian (SAS) AF: 0.00606 AC: 29 AN: 4786

European-Finnish (FIN) AF: 0.0747 AC: 783 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0148 AC: 1002 AN: 67858

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.0123 Hom.: 41

Bravo AF: 0.00993

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0123 AC: 106

ExAC AF: 0.0128 AC: 1525

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	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	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.2
DANN	Benign	0.93
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.29	T
Polyphen		0.015	B
Vest4		0.11
MPC		0.028
ClinPred		0.058	T
GERP RS		1.7
Varity_R		0.060
gMVP		0.17
Mutation Taster		=99/1	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: rs61862390; hg19: chr10-55582127; COSMIC: COSV57376028; COSMIC: COSV57376028;