10-55353860-T-C

Variant names:

• chr10-55353860-T-C
• rs1900493
• NM_001354404.2:c.-155-187209A>G

Variant summary

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

The NM_001354404.2(PCDH15):​c.-155-187209A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,912 control chromosomes in the GnomAD database, including 24,444 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 0.56 (24444 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.334
• Publications: 6 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

ENSG00000236744 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354404.2. 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_001354404.2		c.-155-187209A>G		intron	N/A	NP_001341333.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000613346.4	TSL:4	c.-155-187209A>G		intron	N/A	ENSP00000481211.1	A0A087WXQ6
	ENSG00000236744	ENST00000457975.2	TSL:3	n.305+12232A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84777 AN: 151794 Hom.: 24404 Cov.: 32

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.537

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

GnomAD4 genome AF: 0.559 AC: 84879 AN: 151912 Hom.: 24444 Cov.: 32 AF XY: 0.554 AC XY: 41138 AN XY: 74228

African (AFR) AF: 0.690 AC: 28570 AN: 41432

American (AMR) AF: 0.553 AC: 8424 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1551 AN: 3468

East Asian (EAS) AF: 0.321 AC: 1649 AN: 5138

South Asian (SAS) AF: 0.442 AC: 2134 AN: 4824

European-Finnish (FIN) AF: 0.516 AC: 5445 AN: 10560

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.519 AC: 35275 AN: 67956

Other (OTH) AF: 0.540 AC: 1138 AN: 2108

Alfa AF: 0.515 Hom.: 11883

Bravo AF: 0.568

Asia WGS AF: 0.427 AC: 1487 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.21
DANN	Benign	0.29
PhyloP100		-0.33
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: rs1900493; hg19: chr10-57113620;