10-54571774-A-T

Variant names:

• chr10-54571774-A-T
• rs1930152
• NM_033056.4:c.92-43897T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033056.4(PCDH15):​c.92-43897T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.937 in 152,228 control chromosomes in the GnomAD database, including 67,026 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.94 (67026 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• 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, 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

ENSG00000234173 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.92-43897T>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.92-43897T>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.92-43372T>A		intron	N/A	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.92-43897T>A		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.92-43897T>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.92-43897T>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142467 AN: 152112 Hom.: 66985 Cov.: 32

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.946

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.981

Gnomad OTH AF: 0.944

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.937 AC: 142562 AN: 152228 Hom.: 67026 Cov.: 32 AF XY: 0.936 AC XY: 69671 AN XY: 74426

African (AFR) AF: 0.850 AC: 35286 AN: 41520

American (AMR) AF: 0.914 AC: 13966 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3412 AN: 3472

East Asian (EAS) AF: 0.942 AC: 4884 AN: 5182

South Asian (SAS) AF: 0.947 AC: 4569 AN: 4826

European-Finnish (FIN) AF: 0.990 AC: 10503 AN: 10614

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.981 AC: 66747 AN: 68018

Other (OTH) AF: 0.945 AC: 1995 AN: 2112

Alfa AF: 0.964 Hom.: 3346

Bravo AF: 0.927

Asia WGS AF: 0.905 AC: 3145 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.35
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs1930152; hg19: chr10-56331534;