10-53809469-G-A

Variant names:

• chr10-53809469-G-A
• rs12359240
• ENST00000395445.6:c.4575C>T

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.4596C>T​(p.Ile1532Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,613,842 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (38 hom.)
• Consequence: PCDH15 NM_001142769.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.363
• Publications: 3 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=-0.57).
• BP6: Variant 10-53809469-G-A is Benign according to our data. Variant chr10-53809469-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.363 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00441 (671/152176) while in subpopulation NFE AF = 0.00541 (368/68000). AF 95% confidence interval is 0.00496. There are 4 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown 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.4671+1087C>T		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.4596C>T	p.Ile1532Ile	synonymous	Exon 37 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.4575C>T	p.Ile1525Ile	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.4575C>T	p.Ile1525Ile	synonymous	Exon 35 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000644397.2	MANE Select	c.4671+1087C>T		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4476+1087C>T		intron	N/A	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 670 AN: 152060 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00499 AC: 1240 AN: 248690 AF XY: 0.00511

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00377

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00810

GnomAD4 exome AF: 0.00556 AC: 8122 AN: 1461666 Hom.: 38 Cov.: 33 AF XY: 0.00547 AC XY: 3974 AN XY: 727120

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00411 AC: 184 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 746 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00386 AC: 333 AN: 86256

European-Finnish (FIN) AF: 0.00172 AC: 92 AN: 53398

Middle Eastern (MID) AF: 0.0236 AC: 136 AN: 5768

European-Non Finnish (NFE) AF: 0.00546 AC: 6075 AN: 1111834

Other (OTH) AF: 0.00846 AC: 511 AN: 60374

GnomAD4 genome AF: 0.00441 AC: 671 AN: 152176 Hom.: 4 Cov.: 32 AF XY: 0.00401 AC XY: 298 AN XY: 74380

African (AFR) AF: 0.00118 AC: 49 AN: 41532

American (AMR) AF: 0.00477 AC: 73 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4822

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10578

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68000

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00581 Hom.: 2

Bravo AF: 0.00517

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00735

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.36
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: rs12359240; hg19: chr10-55569229; COSMIC: COSV64673078;