NM_018906.3:c.182C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018906.3(PCDHA3):​c.182C>T​(p.Pro61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,186 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P61Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDHA3
NM_018906.3 missense

Scores

1
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.253
Variant links:
Genes affected
PCDHA3 (HGNC:8669): (protocadherin alpha 3) 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 (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]
PCDHA2 (HGNC:8668): (protocadherin alpha 2) 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 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
PCDHA3NM_018906.3 linkc.182C>T p.Pro61Leu missense_variant Exon 1 of 4 ENST00000522353.3 NP_061729.1 Q9Y5H8-1
PCDHA1NM_018900.4 linkc.2394+12695C>T intron_variant Intron 1 of 3 ENST00000504120.4 NP_061723.1 Q9Y5I3-1
PCDHA2NM_018905.3 linkc.2388+4027C>T intron_variant Intron 1 of 3 ENST00000526136.2 NP_061728.1 Q9Y5H9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDHA3ENST00000522353.3 linkc.182C>T p.Pro61Leu missense_variant Exon 1 of 4 1 NM_018906.3 ENSP00000429808.2 Q9Y5H8-1
PCDHA1ENST00000504120.4 linkc.2394+12695C>T intron_variant Intron 1 of 3 1 NM_018900.4 ENSP00000420840.3 Q9Y5I3-1
PCDHA2ENST00000526136.2 linkc.2388+4027C>T intron_variant Intron 1 of 3 1 NM_018905.3 ENSP00000431748.1 Q9Y5H9-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461186
Hom.:
0
Cov.:
91
AF XY:
0.00000138
AC XY:
1
AN XY:
726922
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:
0.00000180
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
0.22
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;T
Eigen
Benign
0.17
Eigen_PC
Benign
0.095
FATHMM_MKL
Benign
0.35
N
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.46
T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.7
L;L
PROVEAN
Pathogenic
-7.5
D;D
REVEL
Benign
0.15
Sift
Uncertain
0.018
D;T
Sift4G
Uncertain
0.023
D;T
Polyphen
1.0
D;P
Vest4
0.26
MutPred
0.46
Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP
0.63
ClinPred
0.98
D
GERP RS
3.6
Varity_R
0.36
gMVP
0.54

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: rs7731327; hg19: chr5-140180964; API