10-54317438-G-C

Position:

• chr10-54317438-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001384140.1(PCDH15):​c.709C>G​(p.Arg237Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.709C>G	p.Arg237Gly	missense_variant	8/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.709C>G	p.Arg237Gly	missense_variant	8/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.709C>G	p.Arg237Gly	missense_variant	8/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.709C>G	p.Arg237Gly	missense_variant	8/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250784 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461572 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.59	.;.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.6	D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.063	T;.;.;.;.;.;T;T;.;T;.;T;D;.;T;.;.;T;T;T;.;T;T;D
Sift4G	Uncertain	0.0050	D;.;D;D;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4		0.86
MutPred		0.57		Loss of stability (P = 0.167);Loss of stability (P = 0.167);.;Loss of stability (P = 0.167);Loss of stability (P = 0.167);.;Loss of stability (P = 0.167);Loss of stability (P = 0.167);Loss of stability (P = 0.167);Loss of stability (P = 0.167);.;Loss of stability (P = 0.167);Loss of stability (P = 0.167);.;.;.;Loss of stability (P = 0.167);Loss of stability (P = 0.167);Loss of stability (P = 0.167);.;.;Loss of stability (P = 0.167);Loss of stability (P = 0.167);Loss of stability (P = 0.167);
MVP		0.84
MPC		0.22
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.39
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs200798008; hg19: chr10-56077198;