rs2135720

Variant names:

• chr10-53995731-C-G
• rs2135720
• NM_033056.4:c.2786G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-53995731-C-G
• chr10-53995731-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142763.2(PCDH15):​c.2801G>C​(p.Arg934Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R934Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH15 NM_001142763.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850
• Publications: 41 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1746327).

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.2786G>C	p.Arg929Pro	missense	Exon 21 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2786G>C	p.Arg929Pro	missense	Exon 21 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.2801G>C	p.Arg934Pro	missense	Exon 22 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.2786G>C	p.Arg929Pro	missense	Exon 21 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.2786G>C	p.Arg929Pro	missense	Exon 21 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.2807G>C	p.Arg936Pro	missense	Exon 22 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 16023

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.85
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.10
Sift	Benign	0.25	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.45		Gain of catalytic residue at M934 (P = 0.023)
MVP		0.40
MPC		0.035
ClinPred		0.070	T
GERP RS		3.0
Varity_R		0.33
gMVP		0.58
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2135720; hg19: chr10-55755491;