5-141330865-G-C

Variant summary

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

The ENST00000517417.3(PCDHGA1):ā€‹c.181G>Cā€‹(p.Asp61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000015 ( 0 hom. )

Consequence

PCDHGA1
ENST00000517417.3 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.350
Variant links:
Genes affected
PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

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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=0.16801757).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDHGA1NM_018912.3 linkuse as main transcriptc.181G>C p.Asp61His missense_variant 1/4 ENST00000517417.3 NP_061735.1
PCDHGA1NM_031993.2 linkuse as main transcriptc.181G>C p.Asp61His missense_variant 1/1 NP_114382.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDHGA1ENST00000517417.3 linkuse as main transcriptc.181G>C p.Asp61His missense_variant 1/41 NM_018912.3 ENSP00000431083 P1Q9Y5H4-1
PCDHGA1ENST00000378105.4 linkuse as main transcriptc.181G>C p.Asp61His missense_variant 1/1 ENSP00000367345 Q9Y5H4-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251470
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461890
Hom.:
0
Cov.:
30
AF XY:
0.0000179
AC XY:
13
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 25, 2023The c.181G>C (p.D61H) alteration is located in exon 1 (coding exon 1) of the PCDHGA1 gene. This alteration results from a G to C substitution at nucleotide position 181, causing the aspartic acid (D) at amino acid position 61 to be replaced by a histidine (H). 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
0.099
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.094
.;T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.19
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;L
MutationTaster
Benign
1.0
N;N
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.046
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.045
D;T
Polyphen
0.57
P;P
Vest4
0.096
MVP
0.47
MPC
0.77
ClinPred
0.097
T
GERP RS
1.3
Varity_R
0.12
gMVP
0.25

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: rs772633343; hg19: chr5-140710432; API