Genetic Variant NM_033056.4:c.128T>G (chr10-54527841-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_033056.4(PCDH15):c.128T>G(p.Ile43Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,788 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: 6.9e-7 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.62

Variant links:

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 links:

ENSG00000234173 (HGNC:):

ENSG00000234173 links:

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ACMG classification

Classification made for transcript

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, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.128T>G	p.Ile43Arg	missense_variant	Exon 3 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.128T>G	p.Ile43Arg	missense_variant	Exon 3 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.128T>G	p.Ile43Arg	missense_variant	Exon 3 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.128T>G	p.Ile43Arg	missense_variant	Exon 3 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726212

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

0.066

MetaRNN

Pathogenic

0.76

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

-0.47

MutationAssessor

Benign

0.90

.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.0

D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;.;D;D;D;D

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;.;D;D;D;D

Sift4G

Pathogenic

0.0

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Polyphen

0.96, 1.0, 0.99, 0.98, 0.71

.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;.;D;D;P;.

Vest4

0.87

MutPred

0.44

Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);

MVP

0.75

MPC

0.23

ClinPred

0.99

GERP RS

5.7

Varity_R

0.80

gMVP

0.91

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over