chr10-53806693-G-GTCAA

Variant names:

• chr10-53806693-G-GTCAA
• rs770322907
• NM_001384140.1:c.5105_5108dupTTGA

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PVS1_StrongPM2

The NM_001384140.1(PCDH15):c.5105_5108dupTTGA (p.Ser1704fs) variant causes a frameshift, stop gained change. This is a loss-of-function variant that does not trigger NMD. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.0000682 (AC=110) in the gnomAD database across 1,613,728 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000682. Variant has been reported in ClinVar as Uncertain Significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 frameshift, stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.96
• 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 Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 1F

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• Usher syndrome type 1D

  Inheritance: Unknown Classification: LIMITED Submitted by: Natera

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD frameshift: ≥4 pathogenic in truncated region — strong (PVS1 downgraded to PS); Frameshift (exon 38 of 38) at amino acid 1703 of 1740; NMD not predicted. 4 pathogenic variants in the affected exon support its functional importance. A new stop codon is introduced in the shifted frame, truncating the protein to ~1703 amino acids (37 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000682 — very rare for AR gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001384140.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCDH15 NM_001384140.1	MANE Select	c.5105_5108dupTTGA p.Ser1704fs	frameshiftstop_gained	Exon 38 of 38	Prot: NP_001371069.1 UniProt:
	PCDH15 NM_001354429.2		c.5039_5042dupTTGA p.Ser1682fs	frameshiftstop_gained	Exon 37 of 37	Prot: NP_001341358.1
	PCDH15 NM_001142771.2		c.4931_4934dupTTGA p.Ser1646fs	frameshiftstop_gained	Exon 36 of 36	Prot: NP_001136243.1 UniProt:

PCDH15 NM_001384140.1

MANE Select

HGVSc / HGVSpc.5105_5108dupTTGAp.Ser1704fs

Exon rankExon 38 of 38

frameshiftstop_gained

Prot: NP_001371069.1UniProt: Q96QU1-7

PCDH15 NM_001354429.2

HGVSc / HGVSpc.5039_5042dupTTGAp.Ser1682fs

Exon rankExon 37 of 37

frameshiftstop_gained

Prot: NP_001341358.1

PCDH15 NM_001142771.2

HGVSc / HGVSpc.4931_4934dupTTGAp.Ser1646fs

Exon rankExon 36 of 36

frameshiftstop_gained

Prot: NP_001136243.1UniProt: A0A087X1T6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCDH15 ENST00000644397.2	MANE Select	c.5105_5108dupTTGA p.Ser1704fs	frameshiftstop_gained	Exon 38 of 38	Prot: ENSP00000495195.1 UniProt:
	PCDH15 ENST00000616114.4	TSL:1	c.4910_4913dupTTGA p.Ser1639fs	frameshiftstop_gained	Exon 34 of 34	Prot: ENSP00000483745.1 UniProt:
	PCDH15 ENST00000621708.4	TSL:5	c.4931_4934dupTTGA p.Ser1646fs	frameshiftstop_gained	Exon 36 of 36	Prot: ENSP00000484454.1 UniProt:

PCDH15 ENST00000644397.2

MANE Select

HGVSc / HGVSpc.5105_5108dupTTGAp.Ser1704fs

Exon rankExon 38 of 38

frameshiftstop_gained

Prot: ENSP00000495195.1UniProt: Q96QU1-7

PCDH15 ENST00000616114.4

TSL:1

HGVSc / HGVSpc.4910_4913dupTTGAp.Ser1639fs

Exon rankExon 34 of 34

frameshiftstop_gained

Prot: ENSP00000483745.1UniProt: Q96QU1-6

PCDH15 ENST00000621708.4

TSL:5

HGVSc / HGVSpc.4931_4934dupTTGAp.Ser1646fs

Exon rankExon 36 of 36

frameshiftstop_gained

Prot: ENSP00000484454.1UniProt: A0A087X1T6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000723	AC:11	Hom:0	AN:152114	Cov:32
GnomAD2 exomes	AF: 0.0000804	AC:20	Hom:	AN:248696	Cov:
GnomAD4 exome	AF: 0.0000677	AC:99	Hom:0	AN:1461614	Cov:33
GnomAD4 genome	AF: 0.0000723	AC:11	Hom:0	AN:152114	Cov:32
TOPMed (Bravo)	AF: 0.0000982	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000486	AC:4	Hom:0	AN:82272	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	9622	0.0000959 *	1	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.000143	6	41958	0.0000897	6	66888
SCHEMA(Schizophrenia)	0.000115	13	113016	0.0000998	19	190434

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	17/183	disease causing
PhyloP100	Uncertain	6.0

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs770322907;

hg19: chr10-55566453;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar