rs2593107

Variant names:

• chr10-53959892-C-T
• rs2593107
• NM_033056.4:c.3010-48G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.3010-48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,412,740 control chromosomes in the GnomAD database, including 354,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38165 hom., cov: 31)
  • Exomes 𝑓: 0.71 (316663 hom.)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.277
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-53959892-C-T is Benign according to our data. Variant chr10-53959892-C-T is described in ClinVar as Benign. ClinVar VariationId is 262149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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.3010-48G>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3010-48G>A		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.3025-48G>A		intron	N/A	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3010-48G>A		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.3010-48G>A		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.3031-48G>A		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107166 AN: 151918 Hom.: 38144 Cov.: 31

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.735

GnomAD2 exomes AF: 0.744 AC: 180148 AN: 242168 AF XY: 0.739

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.872

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.708 AC: 892354 AN: 1260706 Hom.: 316663 Cov.: 17 AF XY: 0.708 AC XY: 451331 AN XY: 637060

African (AFR) AF: 0.657 AC: 19261 AN: 29316

American (AMR) AF: 0.862 AC: 37993 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 19707 AN: 24900

East Asian (EAS) AF: 0.878 AC: 33768 AN: 38462

South Asian (SAS) AF: 0.734 AC: 59930 AN: 81606

European-Finnish (FIN) AF: 0.720 AC: 38165 AN: 53024

Middle Eastern (MID) AF: 0.757 AC: 4066 AN: 5370

European-Non Finnish (NFE) AF: 0.689 AC: 640881 AN: 930428

Other (OTH) AF: 0.721 AC: 38583 AN: 53524

GnomAD4 genome AF: 0.705 AC: 107240 AN: 152034 Hom.: 38165 Cov.: 31 AF XY: 0.713 AC XY: 53005 AN XY: 74322

African (AFR) AF: 0.646 AC: 26775 AN: 41444

American (AMR) AF: 0.812 AC: 12403 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2731 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4482 AN: 5160

South Asian (SAS) AF: 0.737 AC: 3553 AN: 4822

European-Finnish (FIN) AF: 0.729 AC: 7690 AN: 10554

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47072 AN: 67990

Other (OTH) AF: 0.733 AC: 1549 AN: 2112

Alfa AF: 0.714 Hom.: 7900

Bravo AF: 0.712

Asia WGS AF: 0.780 AC: 2716 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.39
PhyloP100		0.28
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: rs2593107; hg19: chr10-55719652;