chr10-53822161-G-A

Variant names:

• chr10-53822161-G-A
• rs111033445
• NM_033056.4:c.5565C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000644397.2(PCDH15):​c.4368-1931C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,934 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: PCDH15 ENST00000644397.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.279
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-53822161-G-A is Benign according to our data. Variant chr10-53822161-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46503.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644397.2. 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.5565C>T	p.Ala1855Ala	synonymous	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-1931C>T		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.5586C>T	p.Ala1862Ala	synonymous	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.5565C>T	p.Ala1855Ala	synonymous	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000463095.2	TSL:1	n.2584C>T		non_coding_transcript_exon	Exon 10 of 10
	PCDH15	ENST00000644397.2	MANE Select	c.4368-1931C>T		intron	N/A	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 244 AN: 152002 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 251382 AF XY: 0.00172

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00285 AC: 4165 AN: 1461814 Hom.: 11 Cov.: 32 AF XY: 0.00281 AC XY: 2044 AN XY: 727204

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86248

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00347 AC: 3857 AN: 1111952

Other (OTH) AF: 0.00217 AC: 131 AN: 60396

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152120 Hom.: 1 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74356

African (AFR) AF: 0.000506 AC: 21 AN: 41506

American (AMR) AF: 0.00144 AC: 22 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00276 AC: 188 AN: 68004

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00169

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	4	not specified (4)
-	1	-	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.44
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111033445; hg19: chr10-55581921;