rs10740579

Variant names:

• chr10-54317449-G-A
• rs10740579
• NM_033056.4:c.706-8C>T

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.706-8C>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 0.693 in 1,612,902 control chromosomes in the GnomAD database, including 395,521 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38563 hom., cov: 31)
  • Exomes 𝑓: 0.69 (356958 hom.)
• Consequence: PCDH15 NM_001384140.1 splice_region, intron
• Scores: Splicing: ADA: 0.00002108
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.274
• Publications: 13 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.84).
• BP6: Variant 10-54317449-G-A is Benign according to our data. Variant chr10-54317449-G-A is described in ClinVar as Benign. ClinVar VariationId is 46511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.741 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.706-8C>T		splice_region intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.706-8C>T		splice_region intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.721-8C>T		splice_region 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.706-8C>T		splice_region intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.706-8C>T		splice_region intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.706-8C>T		splice_region intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107083 AN: 151820 Hom.: 38522 Cov.: 31

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.657 AC: 164526 AN: 250538 AF XY: 0.660

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.700

Gnomad NFE exome AF: 0.729

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.692 AC: 1011049 AN: 1460964 Hom.: 356958 Cov.: 49 AF XY: 0.691 AC XY: 502447 AN XY: 726804

African (AFR) AF: 0.756 AC: 25309 AN: 33458

American (AMR) AF: 0.615 AC: 27492 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 19667 AN: 26116

East Asian (EAS) AF: 0.190 AC: 7530 AN: 39692

South Asian (SAS) AF: 0.597 AC: 51523 AN: 86238

European-Finnish (FIN) AF: 0.696 AC: 37125 AN: 53360

Middle Eastern (MID) AF: 0.780 AC: 4492 AN: 5760

European-Non Finnish (NFE) AF: 0.716 AC: 796171 AN: 1111298

Other (OTH) AF: 0.692 AC: 41740 AN: 60354

GnomAD4 genome AF: 0.705 AC: 107184 AN: 151938 Hom.: 38563 Cov.: 31 AF XY: 0.698 AC XY: 51822 AN XY: 74232

African (AFR) AF: 0.748 AC: 31001 AN: 41436

American (AMR) AF: 0.678 AC: 10326 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2661 AN: 3466

East Asian (EAS) AF: 0.221 AC: 1138 AN: 5138

South Asian (SAS) AF: 0.580 AC: 2796 AN: 4822

European-Finnish (FIN) AF: 0.690 AC: 7289 AN: 10560

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49401 AN: 67972

Other (OTH) AF: 0.725 AC: 1522 AN: 2098

Alfa AF: 0.729 Hom.: 17148

Bravo AF: 0.707

Asia WGS AF: 0.439 AC: 1528 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.82
DANN	Benign	0.58
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10740579;

hg19: chr10-56077209;

COSMIC: COSV57299868;