10-54213989-G-C

Position:

• chr10-54213989-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384140.1(PCDH15):​c.1045C>G​(p.Leu349Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38443336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1045C>G	p.Leu349Val	missense_variant	10/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1045C>G	p.Leu349Val	missense_variant	10/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1045C>G	p.Leu349Val	missense_variant	10/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1045C>G	p.Leu349Val	missense_variant	10/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459958 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726408

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 11, 2017

The p.Leu349Val variant in PCDH15 has not been previously reported in individual s with hearing loss or Usher syndrome, or in large population studies. Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Leu349Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	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	Benign	0.030	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;N;N;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.14	T;.;.;.;.;.;T;T;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T;T
Sift4G	Benign	0.22	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.30, 0.71, 1.0, 0.77, 0.68	.;.;.;.;.;.;.;.;.;.;.;.;B;.;P;.;.;P;D;D;.;P;P;P
Vest4		0.53
MutPred		0.43		Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);.;Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);.;Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);.;Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);.;.;.;Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);.;.;Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);Loss of phosphorylation at T344 (P = 0.2506);
MVP		0.46
MPC		0.081
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.37
gMVP		0.33

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: rs1554841242; hg19: chr10-55973749;