rs33969792

Variant names:

• chr10-54132841-A-ACACG
• rs33969792
• NM_033056.4:c.1917+33_1917+34insCGTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001384140.1(PCDH15):​c.1917+33_1917+34insCGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1917+33_1917+34insCGTG		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1917+33_1917+34insCGTG		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1932+33_1932+34insCGTG		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.1917+33_1917+34insCGTG		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1917+33_1917+34insCGTG		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1938+33_1938+34insCGTG		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00492 AC: 346 AN: 70282 AF XY: 0.00539

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00382

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 881432 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 437376

African (AFR) AF: 0.00 AC: 0 AN: 17448

American (AMR) AF: 0.00 AC: 0 AN: 29292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15398

East Asian (EAS) AF: 0.00 AC: 0 AN: 34666

South Asian (SAS) AF: 0.00 AC: 0 AN: 53120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 658600

Other (OTH) AF: 0.00 AC: 0 AN: 36520

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs33969792; hg19: chr10-55892601;