10-53823145-G-T

Variant names:

• chr10-53823145-G-T
• rs10825114
• NM_033056.4:c.4581C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033056.4(PCDH15):​c.4581C>A​(p.Pro1527Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,698 control chromosomes in the GnomAD database, including 23,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1527P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2810 hom., cov: 32)
  • Exomes 𝑓: 0.097 (20282 hom.)
• Consequence: PCDH15 NM_033056.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.456
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-53823145-G-T is Benign according to our data. Variant chr10-53823145-G-T is described in ClinVar as Benign. ClinVar VariationId is 46482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.456 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

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.4581C>A	p.Pro1527Pro	synonymous	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2915C>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.4602C>A	p.Pro1534Pro	synonymous	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.4581C>A	p.Pro1527Pro	synonymous	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2915C>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.4388+4248C>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20543 AN: 151936 Hom.: 2807 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0513

Gnomad NFE AF: 0.0521

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.175 AC: 44067 AN: 251142 AF XY: 0.166

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.732

Gnomad FIN exome AF: 0.0691

Gnomad NFE exome AF: 0.0524

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.0969 AC: 141638 AN: 1461644 Hom.: 20282 Cov.: 34 AF XY: 0.0991 AC XY: 72070 AN XY: 727136

African (AFR) AF: 0.185 AC: 6182 AN: 33476

American (AMR) AF: 0.319 AC: 14249 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1160 AN: 26132

East Asian (EAS) AF: 0.778 AC: 30880 AN: 39698

South Asian (SAS) AF: 0.236 AC: 20315 AN: 86252

European-Finnish (FIN) AF: 0.0707 AC: 3775 AN: 53384

Middle Eastern (MID) AF: 0.0571 AC: 329 AN: 5766

European-Non Finnish (NFE) AF: 0.0518 AC: 57571 AN: 1111840

Other (OTH) AF: 0.119 AC: 7177 AN: 60382

GnomAD4 genome AF: 0.135 AC: 20568 AN: 152054 Hom.: 2810 Cov.: 32 AF XY: 0.142 AC XY: 10575 AN XY: 74324

African (AFR) AF: 0.181 AC: 7488 AN: 41474

American (AMR) AF: 0.210 AC: 3208 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.727 AC: 3748 AN: 5154

South Asian (SAS) AF: 0.255 AC: 1231 AN: 4828

European-Finnish (FIN) AF: 0.0734 AC: 777 AN: 10582

Middle Eastern (MID) AF: 0.0517 AC: 15 AN: 290

European-Non Finnish (NFE) AF: 0.0521 AC: 3545 AN: 67990

Other (OTH) AF: 0.136 AC: 287 AN: 2106

Alfa AF: 0.0809 Hom.: 1508

Bravo AF: 0.152

Asia WGS AF: 0.439 AC: 1524 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0496

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.41
PhyloP100		-0.46
Mutation Taster		=100/0	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: rs10825114; hg19: chr10-55582905; COSMIC: COSV57268281; COSMIC: COSV57268281;