Genetic Variant PCDH20:p.Thr836Ala (chr13-61411593-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_022843.4(PCDH20):c.2506A>G(p.Thr836Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDH20
NM_022843.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.20

Variant links:

Genes affected

PCDH20 (HGNC:14257): (protocadherin 20) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. This gene encodes a protein which contains 6 extracellular cadherin domains, a transmembrane domain and a cytoplasmic tail differing from those of the classical cadherins. Although its specific function is undetermined, the cadherin-related neuronal receptor is thought to play a role in the establishment and function of specific cell-cell connections in the brain. [provided by RefSeq, Jul 2008]

PCDH20 links:

ENSG00000197991 (HGNC:):

ENSG00000197991 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH20	NM_022843.4 link	c.2506A>G	p.Thr836Ala	missense_variant	Exon 2 of 2	ENST00000409204.5	NP_073754.2	Q8N6Y1B3KSZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH20	ENST00000409204.5 link	c.2506A>G	p.Thr836Ala	missense_variant	Exon 2 of 2	1	NM_022843.4	ENSP00000387250.3		Q8N6Y1
ENSG00000197991	ENST00000409186.1 link	c.2506A>G	p.Thr836Ala	missense_variant	Exon 5 of 5	1		ENSP00000386653.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2506A>G (p.T836A) alteration is located in exon 2 (coding exon 2) of the PCDH20 gene. This alteration results from a A to G substitution at nucleotide position 2506, causing the threonine (T) at amino acid position 836 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;.

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.36

Sift

Benign

0.056

T;T

Sift4G

Benign

0.11

T;T

Vest4

0.75

MutPred

0.52

Gain of catalytic residue at L833 (P = 9e-04);Gain of catalytic residue at L833 (P = 9e-04);

MVP

0.60

MPC

0.78

ClinPred

0.97

GERP RS

5.8

Varity_R

0.25

gMVP

0.70

Mutation Taster

=52/48

polymorphism

(source)

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

Below is the list of publications found by LitVar for variant 13:61411593 T>C . It may be empty.

13-61411593-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over