rs139441645

Variant names:

• chr10-53808767-C-T
• rs139441645
• ENST00000395445.6:c.5277G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-53808767-C-T
• chr10-53808767-C-A

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.5298G>A​(p.Ala1766Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,612,442 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (52 hom.)
• Consequence: PCDH15 NM_001142769.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.507
• Publications: 2 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=-0.6).
• BP6: Variant 10-53808767-C-T is Benign according to our data. Variant chr10-53808767-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.507 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00702 (1068/152200) while in subpopulation NFE AF = 0.00824 (560/68000). AF 95% confidence interval is 0.00767. There are 6 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.4672-1637G>A		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.5298G>A	p.Ala1766Ala	synonymous	Exon 37 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.5277G>A	p.Ala1759Ala	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.5277G>A	p.Ala1759Ala	synonymous	Exon 35 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000644397.2	MANE Select	c.4672-1637G>A		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4477-1637G>A		intron	N/A	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1067 AN: 152082 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00662

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00699 AC: 1718 AN: 245870 AF XY: 0.00693

Gnomad AFR exome AF: 0.00741

Gnomad AMR exome AF: 0.000704

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00796 AC: 11629 AN: 1460242 Hom.: 52 Cov.: 31 AF XY: 0.00776 AC XY: 5636 AN XY: 726220

African (AFR) AF: 0.00816 AC: 273 AN: 33458

American (AMR) AF: 0.000742 AC: 33 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85852

European-Finnish (FIN) AF: 0.0195 AC: 1039 AN: 53336

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00884 AC: 9825 AN: 1111288

Other (OTH) AF: 0.00638 AC: 385 AN: 60322

GnomAD4 genome AF: 0.00702 AC: 1068 AN: 152200 Hom.: 6 Cov.: 32 AF XY: 0.00764 AC XY: 568 AN XY: 74390

African (AFR) AF: 0.00662 AC: 275 AN: 41540

American (AMR) AF: 0.00203 AC: 31 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00824 AC: 560 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00705 Hom.: 1

Bravo AF: 0.00566

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		-0.51
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: rs139441645; hg19: chr10-55568527;