rs397517462

Variant names:

• chr10-53822469-TAGGAGG-T
• rs397517462
• NM_033056.4:c.5251_5256delCCTCCT

Your query was ambiguous. Multiple possible variants found:

• chr10-53822469-TAGGAGG-T
• chr10-53822469-TAGGAGG-TAGG
• chr10-53822469-TAGGAGG-TAGGAGGAGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_033056.4(PCDH15):​c.5251_5256delCCTCCT​(p.Pro1751_Pro1752del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,599,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1751P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PCDH15 NM_033056.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11
• 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, LIMITED Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_033056.4

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.5251_5256delCCTCCT	p.Pro1751_Pro1752del	conservative_inframe_deletion	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2245_4368-2240delCCTCCT		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.5272_5277delCCTCCT	p.Pro1758_Pro1759del	conservative_inframe_deletion	Exon 35 of 35	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.5251_5256delCCTCCT	p.Pro1751_Pro1752del	conservative_inframe_deletion	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2245_4368-2240delCCTCCT		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4388+4918_4388+4923delCCTCCT		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000204

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000257 AC: 6 AN: 233792 AF XY: 0.0000157

Gnomad AFR exome AF: 0.0000693

Gnomad AMR exome AF: 0.000148

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: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1453324 Hom.: 0 AF XY: 0.0000111 AC XY: 8 AN XY: 722638

African (AFR) AF: 0.00 AC: 0 AN: 33052

American (AMR) AF: 0.000113 AC: 5 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39030

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107854

Other (OTH) AF: 0.0000167 AC: 1 AN: 60032

GnomAD4 genome AF: 0.0000206 AC: 3 AN: 145736 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 70940

African (AFR) AF: 0.0000509 AC: 2 AN: 39292

American (AMR) AF: 0.00 AC: 0 AN: 14512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4910

South Asian (SAS) AF: 0.00 AC: 0 AN: 4504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66058

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=173/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397517462; hg19: chr10-55582229;