rs111033436

Variant names:

• chr10-54213995-G-A
• rs111033436
• NM_033056.4:c.1039C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-54213995-G-A
• chr10-54213995-G-C
• chr10-54213995-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001384140.1(PCDH15):​c.1039C>T​(p.Leu347Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00397 in 1,612,234 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (40 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 7.14
• Publications: 17 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059919655).
• BP6: Variant 10-54213995-G-A is Benign according to our data. Variant chr10-54213995-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46434.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

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.1039C>T	p.Leu347Phe	missense	Exon 10 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1039C>T	p.Leu347Phe	missense	Exon 10 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1054C>T	p.Leu352Phe	missense	Exon 11 of 35	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.1039C>T	p.Leu347Phe	missense	Exon 10 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1039C>T	p.Leu347Phe	missense	Exon 10 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1039C>T	p.Leu347Phe	missense	Exon 10 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152182 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00380 AC: 956 AN: 251374 AF XY: 0.00403

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00405 AC: 5913 AN: 1459934 Hom.: 40 Cov.: 30 AF XY: 0.00416 AC XY: 3019 AN XY: 726346

African (AFR) AF: 0.000748 AC: 25 AN: 33432

American (AMR) AF: 0.00197 AC: 88 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 439 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00302 AC: 260 AN: 86216

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53358

Middle Eastern (MID) AF: 0.00504 AC: 29 AN: 5752

European-Non Finnish (NFE) AF: 0.00427 AC: 4744 AN: 1110464

Other (OTH) AF: 0.00454 AC: 274 AN: 60314

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152300 Hom.: 3 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74456

African (AFR) AF: 0.000794 AC: 33 AN: 41560

American (AMR) AF: 0.00288 AC: 44 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00457 AC: 311 AN: 68024

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00458 Hom.: 9

Bravo AF: 0.00331

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00361 AC: 438

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.71
MPC		0.21
ClinPred		0.010	T
GERP RS		5.0
Varity_R		0.50
gMVP		0.65
Mutation Taster		=87/13	polymorphism

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: rs111033436; hg19: chr10-55973755; COSMIC: COSV105882550;