rs397517460

Variant names:

• chr10-53823134-T-C
• rs397517460
• NM_033056.4:c.4592A>G

Variant summary

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

The NM_033056.4(PCDH15):​c.4592A>G​(p.Glu1531Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

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, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.4592A>G	p.Glu1531Gly	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-2904A>G		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4592A>G	p.Glu1531Gly	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4368-2904A>G		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251164 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135762

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Glu1531Gly vari ant has not been reported in the literature nor previously identified by our lab oratory. The Glu (Glutamic acid) residue is conserved across mammals and computa tional analyses (PolyPhen, AlignGVGD) suggest that the Glu1531Gly variant may im pact the protein. However, this information is not predictive enough to assume p athogenicity. It should be noted that this lab has only sequenced the PCDH15 gen e in 138 individuals such that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a benig n variant. In summary, the clinical significance of this variant cannot be deter mined with certainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	15
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.044	.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D;.;.;N;D;N;.;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.;.;D;D;D;.;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D;D
Polyphen		0.77	P;.;.;P;P;P;.;D;P
Vest4		0.72
MutPred		0.54		.;.;.;Loss of stability (P = 0.0143);.;.;.;.;.;
MVP		0.85
MPC		0.14
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.45

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: rs397517460; hg19: chr10-55582894;