10-53822421-GAGGAGGAGC-GAGGAGGAGCAGGAGGAGC

Variant names:

• chr10-53822421-G-GAGGAGGAGC
• rs397517466
• NM_033056.4:c.5296_5304dupGCTCCTCCT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_033056.4(PCDH15):​c.5296_5304dupGCTCCTCCT​(p.Pro1768_Pro1769insAlaProPro) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,584,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1768P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PCDH15 NM_033056.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.318
• 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, 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: Likely_benign. The variant received -1 ACMG points.

• 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.5296_5304dupGCTCCTCCT	p.Pro1768_Pro1769insAlaProPro	conservative_inframe_insertion	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2200_4368-2192dupGCTCCTCCT		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.5317_5325dupGCTCCTCCT	p.Pro1775_Pro1776insAlaProPro	conservative_inframe_insertion	Exon 35 of 35	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5296_5304dupGCTCCTCCT	p.Pro1768_Pro1769insAlaProPro	conservative_inframe_insertion	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2200_4368-2192dupGCTCCTCCT		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.4388+4963_4388+4971dupGCTCCTCCT		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 26 AN: 151432 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000921

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000135 AC: 27 AN: 200468 AF XY: 0.000147

Gnomad AFR exome AF: 0.0000846

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000959

Gnomad OTH exome AF: 0.000751

GnomAD4 exome AF: 0.000120 AC: 172 AN: 1432852 Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 91 AN XY: 710618

African (AFR) AF: 0.0000313 AC: 1 AN: 31988

American (AMR) AF: 0.000395 AC: 16 AN: 40462

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51572

Middle Eastern (MID) AF: 0.00196 AC: 11 AN: 5622

European-Non Finnish (NFE) AF: 0.0000875 AC: 96 AN: 1097318

Other (OTH) AF: 0.000775 AC: 46 AN: 59360

GnomAD4 genome AF: 0.000172 AC: 26 AN: 151550 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74112

African (AFR) AF: 0.0000487 AC: 2 AN: 41096

American (AMR) AF: 0.000920 AC: 14 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67918

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	-	1	not specified (1)
-	1	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397517466; hg19: chr10-55582181;