10-54189391-G-A

Variant names:

• chr10-54189391-G-A
• rs16905686
• NM_033056.4:c.1306-4123C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001142769.3(PCDH15):​c.1321-7C>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 0.172 in 1,522,380 control chromosomes in the GnomAD database, including 36,148 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 0.17 (3757 hom., cov: 32)
  • Exomes 𝑓: 0.17 (32391 hom.)
• Consequence: PCDH15 NM_001142769.3 splice_region, intron
• Scores: Splicing: ADA: 0.0009823
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.18
• Publications: 16 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-54189391-G-A is Benign according to our data. Variant chr10-54189391-G-A is described in ClinVar as Benign. ClinVar VariationId is 44031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142769.3. 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.1306-4123C>T		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1306-4123C>T		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1321-4123C>T		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.1306-4123C>T		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1306-4123C>T		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1306-7C>T		splice_region intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26488 AN: 151684 Hom.: 3756 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.235 AC: 40068 AN: 170490 AF XY: 0.237

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.841

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.172 AC: 235065 AN: 1370578 Hom.: 32391 Cov.: 27 AF XY: 0.176 AC XY: 119500 AN XY: 678250

African (AFR) AF: 0.121 AC: 3727 AN: 30822

American (AMR) AF: 0.269 AC: 9094 AN: 33786

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3355 AN: 24030

East Asian (EAS) AF: 0.869 AC: 31806 AN: 36612

South Asian (SAS) AF: 0.339 AC: 24628 AN: 72554

European-Finnish (FIN) AF: 0.145 AC: 7256 AN: 50094

Middle Eastern (MID) AF: 0.198 AC: 1089 AN: 5510

European-Non Finnish (NFE) AF: 0.135 AC: 142832 AN: 1060524

Other (OTH) AF: 0.199 AC: 11278 AN: 56646

GnomAD4 genome AF: 0.175 AC: 26498 AN: 151802 Hom.: 3757 Cov.: 32 AF XY: 0.185 AC XY: 13707 AN XY: 74180

African (AFR) AF: 0.127 AC: 5263 AN: 41460

American (AMR) AF: 0.212 AC: 3233 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3466

East Asian (EAS) AF: 0.842 AC: 4329 AN: 5140

South Asian (SAS) AF: 0.369 AC: 1776 AN: 4818

European-Finnish (FIN) AF: 0.143 AC: 1508 AN: 10528

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9378 AN: 67848

Other (OTH) AF: 0.178 AC: 373 AN: 2100

Alfa AF: 0.145 Hom.: 3005

Bravo AF: 0.181

Asia WGS AF: 0.572 AC: 1976 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00098
dbscSNV1_RF	Benign	0.034
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: rs16905686; hg19: chr10-55949151; COSMIC: COSV107334606;