rs114137983

Variant names:

• chr10-53822312-G-A
• rs114137983
• NM_033056.4:c.5414C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-53822312-G-A
• chr10-53822312-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001142763.2(PCDH15):​c.5435C>T​(p.Pro1812Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,609,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1812P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: PCDH15 NM_001142763.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.56
• Publications: 6 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, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047721267).
• BP6: Variant 10-53822312-G-A is Benign according to our data. Variant chr10-53822312-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46500.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00208 (316/152020) while in subpopulation AFR AF = 0.006 (249/41494). AF 95% confidence interval is 0.00539. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142763.2. 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.5414C>T	p.Pro1805Leu	missense	Exon 33 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.4368-2082C>T		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.5435C>T	p.Pro1812Leu	missense	Exon 35 of 35	NP_001136235.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5414C>T	p.Pro1805Leu	missense	Exon 33 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.4368-2082C>T		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.4388+5081C>T		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 317 AN: 151902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00385

GnomAD2 exomes AF: 0.00107 AC: 255 AN: 238988 AF XY: 0.000921

Gnomad AFR exome AF: 0.00700

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000709

Gnomad EAS exome AF: 0.000684

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000581 AC: 847 AN: 1457338 Hom.: 2 Cov.: 32 AF XY: 0.000542 AC XY: 393 AN XY: 724566

African (AFR) AF: 0.00741 AC: 247 AN: 33354

American (AMR) AF: 0.00222 AC: 97 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26084

East Asian (EAS) AF: 0.00126 AC: 50 AN: 39574

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85918

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 53220

Middle Eastern (MID) AF: 0.00522 AC: 30 AN: 5748

European-Non Finnish (NFE) AF: 0.000292 AC: 324 AN: 1109430

Other (OTH) AF: 0.00123 AC: 74 AN: 60224

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.00194 AC XY: 144 AN XY: 74312

African (AFR) AF: 0.00600 AC: 249 AN: 41494

American (AMR) AF: 0.00184 AC: 28 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67968

Other (OTH) AF: 0.00381 AC: 8 AN: 2100

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00636 AC: 28

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000957 AC: 116

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	PCDH15-related disorder (1)
-	1	-	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.0
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.45	B
Vest4		0.10
MVP		0.74
MPC		0.028
ClinPred		0.053	T
GERP RS		3.5
Varity_R		0.066
gMVP		0.20
Mutation Taster		=88/12	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: rs114137983; hg19: chr10-55582072;