chr10-53808770-T-C

Variant names:

• chr10-53808770-T-C
• rs145178582
• ENST00000395445.6:c.5274A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001142769.3(PCDH15):​c.5295A>G​(p.Pro1765Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,612,516 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: PCDH15 NM_001142769.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.642
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-53808770-T-C is Benign according to our data. Variant chr10-53808770-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.642 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00217 (331/152258) while in subpopulation AFR AF = 0.0076 (316/41568). AF 95% confidence interval is 0.00691. There are 2 homozygotes in GnomAd4. There are 152 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_001142769.3. 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_001384140.1	MANE Select	c.4672-1640A>G		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.5295A>G	p.Pro1765Pro	synonymous	Exon 37 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.5274A>G	p.Pro1758Pro	synonymous	Exon 35 of 35	NP_001341340.1	Q96QU1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000395445.6	TSL:1	c.5274A>G	p.Pro1758Pro	synonymous	Exon 35 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000644397.2	MANE Select	c.4672-1640A>G		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4477-1640A>G		intron	N/A	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000525 AC: 129 AN: 245864 AF XY: 0.000449

Gnomad AFR exome AF: 0.00809

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000256 AC: 374 AN: 1460258 Hom.: 4 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 726230

African (AFR) AF: 0.00935 AC: 313 AN: 33460

American (AMR) AF: 0.000360 AC: 16 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111326

Other (OTH) AF: 0.000696 AC: 42 AN: 60328

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74426

African (AFR) AF: 0.00760 AC: 316 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00250

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	PCDH15-related disorder (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
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.64
PhyloP100		-0.64
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: rs145178582; hg19: chr10-55568530;