rs2680324

Variant names:

• chr10-55210311-T-G
• rs2680324
• NM_001354404.2:c.-155-43660A>C

Variant summary

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

The NM_001354404.2(PCDH15):​c.-155-43660A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 151,818 control chromosomes in the GnomAD database, including 35,352 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 0.68 (35352 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.245
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2	c.-155-43660A>C		intron_variant	Intron 2 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000458638.1	c.-155-43660A>C		intron_variant	Intron 1 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4	c.-155-43660A>C		intron_variant	Intron 2 of 5	4		ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.680 AC: 103110 AN: 151700 Hom.: 35297 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.680 AC: 103220 AN: 151818 Hom.: 35352 Cov.: 32 AF XY: 0.678 AC XY: 50354 AN XY: 74216

African (AFR) AF: 0.768 AC: 31735 AN: 41344

American (AMR) AF: 0.662 AC: 10086 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3185 AN: 5160

South Asian (SAS) AF: 0.665 AC: 3210 AN: 4824

European-Finnish (FIN) AF: 0.655 AC: 6888 AN: 10516

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43910 AN: 67962

Other (OTH) AF: 0.639 AC: 1344 AN: 2104

Alfa AF: 0.674 Hom.: 4524

Bravo AF: 0.684

Asia WGS AF: 0.701 AC: 2429 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.8
DANN	Benign	0.73
PhyloP100		-0.24
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: rs2680324; hg19: chr10-56970071;