10-53866870-GAA-GA

Variant names:

• chr10-53866870-GA-G
• rs5785023
• NM_033056.4:c.3502-14delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001384140.1(PCDH15):​c.3502-14delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,480,142 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.936
• 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 -16 ACMG points.

• BP6: Variant 10-53866870-GA-G is Benign according to our data. Variant chr10-53866870-GA-G is described in ClinVar as Benign. ClinVar VariationId is 179543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (415/150054) while in subpopulation AFR AF = 0.00802 (329/41008). AF 95% confidence interval is 0.00731. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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.3502-14delT		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3502-14delT		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.3517-14delT		intron	N/A	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.3502-14delT		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.3502-14delT		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.3523-14delT		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 414 AN: 149950 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00802

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000996

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00755

Gnomad FIN AF: 0.000399

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.00189 AC: 439 AN: 232130 AF XY: 0.00204

Gnomad AFR exome AF: 0.00869

Gnomad AMR exome AF: 0.000541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000629

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.000462

Gnomad OTH exome AF: 0.000538

GnomAD4 exome AF: 0.00106 AC: 1404 AN: 1330088 Hom.: 11 Cov.: 23 AF XY: 0.00122 AC XY: 815 AN XY: 668006

African (AFR) AF: 0.00826 AC: 243 AN: 29420

American (AMR) AF: 0.000711 AC: 30 AN: 42170

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24926

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34290

South Asian (SAS) AF: 0.00783 AC: 637 AN: 81340

European-Finnish (FIN) AF: 0.000115 AC: 6 AN: 52284

Middle Eastern (MID) AF: 0.00184 AC: 10 AN: 5430

European-Non Finnish (NFE) AF: 0.000410 AC: 412 AN: 1004750

Other (OTH) AF: 0.00115 AC: 64 AN: 55478

GnomAD4 genome AF: 0.00277 AC: 415 AN: 150054 Hom.: 1 Cov.: 22 AF XY: 0.00278 AC XY: 203 AN XY: 73118

African (AFR) AF: 0.00802 AC: 329 AN: 41008

American (AMR) AF: 0.000995 AC: 15 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00799 AC: 38 AN: 4758

European-Finnish (FIN) AF: 0.000399 AC: 4 AN: 10024

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000327 AC: 22 AN: 67366

Other (OTH) AF: 0.00144 AC: 3 AN: 2078

Alfa AF: 0.000724 Hom.: 212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94
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: rs5785023; hg19: chr10-55626630; COSMIC: COSV57272352;