rs41304641

Variant names:

• chr10-54346487-G-A
• rs41304641
• NM_033056.4:c.475-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001142763.2(PCDH15):​c.490-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,090 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (91 hom.)
• Consequence: PCDH15 NM_001142763.2 splice_region, intron
• Scores: Splicing: ADA: 0.06887
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.21
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 10-54346487-G-A is Benign according to our data. Variant chr10-54346487-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00804 (1224/152146) while in subpopulation NFE AF = 0.011 (749/67982). AF 95% confidence interval is 0.0104. There are 10 homozygotes in GnomAd4. There are 578 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.475-3C>T		splice_region intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.475-3C>T		splice_region intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.490-3C>T		splice_region intron	N/A	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.475-3C>T		splice_region intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.475-3C>T		splice_region intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.475-3C>T		splice_region intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1224 AN: 152028 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00492

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00831 AC: 2087 AN: 251012 AF XY: 0.00865

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00761

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.00935 AC: 13659 AN: 1460944 Hom.: 91 Cov.: 31 AF XY: 0.00934 AC XY: 6787 AN XY: 726796

African (AFR) AF: 0.00137 AC: 46 AN: 33458

American (AMR) AF: 0.00812 AC: 363 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 822 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39648

South Asian (SAS) AF: 0.00395 AC: 341 AN: 86244

European-Finnish (FIN) AF: 0.00375 AC: 199 AN: 53016

Middle Eastern (MID) AF: 0.00781 AC: 45 AN: 5762

European-Non Finnish (NFE) AF: 0.0102 AC: 11340 AN: 1111628

Other (OTH) AF: 0.00830 AC: 501 AN: 60368

GnomAD4 genome AF: 0.00804 AC: 1224 AN: 152146 Hom.: 10 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74408

African (AFR) AF: 0.00166 AC: 69 AN: 41520

American (AMR) AF: 0.00850 AC: 130 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4818

European-Finnish (FIN) AF: 0.00492 AC: 52 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 749 AN: 67982

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00966 Hom.: 7

Bravo AF: 0.00846

EpiCase AF: 0.0123

EpiControl AF: 0.0131

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	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	-0.30
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		2.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.069
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.010		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: rs41304641; hg19: chr10-56106247; COSMIC: COSV57416707;