chr10-53809212-T-G

Variant names:

• chr10-53809212-T-G
• rs11003863
• ENST00000395445.6:c.4832A>C

Variant summary

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

The NM_001142769.3(PCDH15):​c.4853A>C​(p.Glu1618Ala) variant causes a missense change. The variant allele was found at a frequency of 0.196 in 1,613,746 control chromosomes in the GnomAD database, including 40,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1618D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3674 hom., cov: 32)
  • Exomes 𝑓: 0.20 (37238 hom.)
• Consequence: PCDH15 NM_001142769.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.64
• Publications: 28 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 (MetaRNN=3.748185E-6).
• BP6: Variant 10-53809212-T-G is Benign according to our data. Variant chr10-53809212-T-G is described in ClinVar as Benign. ClinVar VariationId is 44035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 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_001384140.1	MANE Select	c.4671+1344A>C		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.4853A>C	p.Glu1618Ala	missense	Exon 37 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.4832A>C	p.Glu1611Ala	missense	Exon 35 of 35	NP_001341340.1	Q96QU1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000395445.6	TSL:1	c.4832A>C	p.Glu1611Ala	missense	Exon 35 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000644397.2	MANE Select	c.4671+1344A>C		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4476+1344A>C		intron	N/A	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28359 AN: 152004 Hom.: 3676 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.254 AC: 63144 AN: 248664 AF XY: 0.249

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.703

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.197 AC: 288518 AN: 1461626 Hom.: 37238 Cov.: 34 AF XY: 0.200 AC XY: 145478 AN XY: 727082

African (AFR) AF: 0.115 AC: 3851 AN: 33480

American (AMR) AF: 0.374 AC: 16710 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4699 AN: 26136

East Asian (EAS) AF: 0.741 AC: 29407 AN: 39696

South Asian (SAS) AF: 0.320 AC: 27625 AN: 86250

European-Finnish (FIN) AF: 0.173 AC: 9247 AN: 53386

Middle Eastern (MID) AF: 0.132 AC: 764 AN: 5768

European-Non Finnish (NFE) AF: 0.165 AC: 183777 AN: 1111830

Other (OTH) AF: 0.206 AC: 12438 AN: 60374

GnomAD4 genome AF: 0.186 AC: 28368 AN: 152120 Hom.: 3674 Cov.: 32 AF XY: 0.194 AC XY: 14444 AN XY: 74370

African (AFR) AF: 0.117 AC: 4849 AN: 41526

American (AMR) AF: 0.265 AC: 4042 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 675 AN: 3466

East Asian (EAS) AF: 0.697 AC: 3583 AN: 5138

South Asian (SAS) AF: 0.328 AC: 1580 AN: 4818

European-Finnish (FIN) AF: 0.170 AC: 1799 AN: 10584

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11217 AN: 68000

Other (OTH) AF: 0.189 AC: 399 AN: 2114

Alfa AF: 0.183 Hom.: 7620

Bravo AF: 0.194

TwinsUK AF: 0.161 AC: 598

ALSPAC AF: 0.172 AC: 664

ESP6500AA AF: 0.121 AC: 381

ESP6500EA AF: 0.161 AC: 1150

ExAC AF: 0.249 AC: 29937

Asia WGS AF: 0.441 AC: 1532 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.161

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0000038	T
MetaSVM	Benign	-0.92	T
PhyloP100		4.6
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.051
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.038	D
Vest4		0.31
ClinPred		0.029	T
GERP RS		4.6
Mutation Taster		=95/5	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: rs11003863; hg19: chr10-55568972; COSMIC: COSV64696777;