chr10-54778999-G-T

Variant names:

• chr10-54778999-G-T
• rs1912985
• NM_033056.4:c.-29+21926C>A

Variant summary

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

The NM_001142763.2(PCDH15):​c.-29+21926C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 151,806 control chromosomes in the GnomAD database, including 3,874 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 0.21 (3874 hom., cov: 31)
• Consequence: PCDH15 NM_001142763.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142763.2. 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.-29+21926C>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.-29+21926C>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.-29+21926C>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.-29+21926C>A		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.-29+21926C>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.-29+21926C>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32123 AN: 151688 Hom.: 3851 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.212 AC: 32181 AN: 151806 Hom.: 3874 Cov.: 31 AF XY: 0.219 AC XY: 16280 AN XY: 74194

African (AFR) AF: 0.212 AC: 8786 AN: 41410

American (AMR) AF: 0.359 AC: 5465 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2292 AN: 5124

South Asian (SAS) AF: 0.294 AC: 1417 AN: 4818

European-Finnish (FIN) AF: 0.173 AC: 1824 AN: 10554

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10877 AN: 67890

Other (OTH) AF: 0.222 AC: 467 AN: 2106

Alfa AF: 0.182 Hom.: 9031

Bravo AF: 0.228

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.028
DANN	Benign	0.37
PhyloP100		-2.4
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: rs1912985; hg19: chr10-56538759;