NM_033056.4:c.3316C>G

Variant names:

• chr10-53938872-G-C
• rs202033121
• NM_033056.4:c.3316C>G

Variant summary

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

The NM_033056.4(PCDH15):​c.3316C>G​(p.Arg1106Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1106P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.3316C>G	p.Arg1106Gly	missense	Exon 25 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3316C>G	p.Arg1106Gly	missense	Exon 25 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.3331C>G	p.Arg1111Gly	missense	Exon 26 of 35	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3316C>G	p.Arg1106Gly	missense	Exon 25 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3316C>G	p.Arg1106Gly	missense	Exon 25 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3337C>G	p.Arg1113Gly	missense	Exon 26 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461318 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726990

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111622

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	D
Vest4		0.86
MutPred		0.64		Gain of catalytic residue at V1107 (P = 0.0336)
MVP		0.81
MPC		0.23
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.36
gMVP		0.69
Mutation Taster		=40/60	disease causing

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: rs202033121; hg19: chr10-55698632;