Genetic Variant PCDHA1:p.Ala166Gly (chr5-140786787-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018900.4(PCDHA1):c.497C>G(p.Ala166Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PCDHA1
NM_018900.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.13

Variant links:

Genes affected

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 links:

ENSG00000279726 (HGNC:):

ENSG00000279726 links:

PCDHA@ (HGNC:8662):

PCDHA@ links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13754201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1	Q9Y5I3-1
PCDHA1	NM_031410.2 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 1		NP_113598.1	Q9Y5I3-3
PCDHA1	NM_031411.3 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 4		NP_113599.1	Q9Y5I3-2
PCDHA@		n.140786787C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHA1	ENST00000504120.4 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3	Q9Y5I3-1
PCDHA1	ENST00000394633.7 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 4	1		ENSP00000378129.3	Q9Y5I3-2
PCDHA1	ENST00000378133.4 link	c.497C>G	p.Ala166Gly	missense_variant	Exon 1 of 1	6		ENSP00000367373.3	Q9Y5I3-3
ENSG00000279726	ENST00000655235.1 link	n.2725G>C		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251268

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135858

show subpopulations

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727238

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:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.63

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.0056

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.53

N;N;N

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.11

Sift

Benign

0.033

D;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.048

B;B;B

Vest4

0.086

MutPred

0.65

Loss of catalytic residue at A166 (P = 0.0389);Loss of catalytic residue at A166 (P = 0.0389);Loss of catalytic residue at A166 (P = 0.0389);

MVP

0.40

MPC

0.35

ClinPred

0.13

GERP RS

4.1

Varity_R

0.22

gMVP

0.12

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. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over