5-140788566-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018900.4(PCDHA1):​c.2276G>C​(p.Cys759Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C759F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PCDHA1
NM_018900.4 missense

Scores

2
3
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.62
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]

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ACMG classification

Classification made for transcript

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=0.40703285).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDHA1NM_018900.4 linkc.2276G>C p.Cys759Ser missense_variant Exon 1 of 4 ENST00000504120.4 NP_061723.1 Q9Y5I3-1
PCDHA1NM_031410.2 linkc.2276G>C p.Cys759Ser missense_variant Exon 1 of 1 NP_113598.1 Q9Y5I3-3
PCDHA1NM_031411.3 linkc.1602+674G>C intron_variant Intron 1 of 3 NP_113599.1 Q9Y5I3-2
PCDHA@ n.140788566G>C intragenic_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDHA1ENST00000504120.4 linkc.2276G>C p.Cys759Ser missense_variant Exon 1 of 4 1 NM_018900.4 ENSP00000420840.3 Q9Y5I3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461640
Hom.:
0
Cov.:
59
AF XY:
0.00000138
AC XY:
1
AN XY:
727108
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
21
DANN
Benign
0.94
DEOGEN2
Uncertain
0.46
.;T
Eigen
Benign
0.048
Eigen_PC
Benign
0.033
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.73
T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.41
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Pathogenic
3.5
M;M
PROVEAN
Pathogenic
-7.5
D;D
REVEL
Benign
0.20
Sift
Uncertain
0.011
D;D
Sift4G
Benign
0.12
T;T
Polyphen
0.26
B;B
Vest4
0.48
MutPred
0.37
Gain of phosphorylation at C759 (P = 0.0087);Gain of phosphorylation at C759 (P = 0.0087);
MVP
0.61
MPC
0.45
ClinPred
0.95
D
GERP RS
4.3
Varity_R
0.53
gMVP
0.46

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.

Other links and lift over

dbSNP: rs2240695; hg19: chr5-140168151; API