rs727503363

Variant names:

• chr10-53822448-GAGGAGGAGA-G
• rs727503363
• NM_033056.4:c.5269_5277delTCTCCTCCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_033056.4(PCDH15):​c.5269_5277delTCTCCTCCT​(p.Ser1757_Pro1759del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00058 in 1,597,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1757S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: PCDH15 NM_033056.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.32
• 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, 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_033056.4
• BP6: Variant 10-53822448-GAGGAGGAGA-G is Benign according to our data. Variant chr10-53822448-GAGGAGGAGA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.5269_5277delTCTCCTCCT	p.Ser1757_Pro1759del	conservative_inframe_deletion	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2227_4368-2219delTCTCCTCCT		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.5290_5298delTCTCCTCCT	p.Ser1764_Pro1766del	conservative_inframe_deletion	Exon 35 of 35	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5269_5277delTCTCCTCCT	p.Ser1757_Pro1759del	conservative_inframe_deletion	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000463095.2	TSL:1	n.2288_2296delTCTCCTCCT		non_coding_transcript_exon	Exon 10 of 10
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2227_4368-2219delTCTCCTCCT		intron	N/A	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 45 AN: 151224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000343 AC: 76 AN: 221474 AF XY: 0.000357

Gnomad AFR exome AF: 0.000301

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000124

Gnomad FIN exome AF: 0.0000492

Gnomad NFE exome AF: 0.000630

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.000609 AC: 881 AN: 1445732 Hom.: 0 AF XY: 0.000581 AC XY: 417 AN XY: 718148

African (AFR) AF: 0.000650 AC: 21 AN: 32326

American (AMR) AF: 0.0000697 AC: 3 AN: 43032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.000157 AC: 6 AN: 38270

South Asian (SAS) AF: 0.0000946 AC: 8 AN: 84570

European-Finnish (FIN) AF: 0.0000577 AC: 3 AN: 52020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.000706 AC: 779 AN: 1104074

Other (OTH) AF: 0.00102 AC: 61 AN: 59762

GnomAD4 genome AF: 0.000297 AC: 45 AN: 151340 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 73978

African (AFR) AF: 0.000294 AC: 12 AN: 40848

American (AMR) AF: 0.000131 AC: 2 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67936

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000348

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=143/57	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503363; hg19: chr10-55582208;