5-141355704-G-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000571252.3(PCDHGA4):āc.597G>Cā(p.Gln199His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
PCDHGA4
ENST00000571252.3 missense
ENST00000571252.3 missense
Scores
6
4
Clinical Significance
Conservation
PhyloP100: -0.167
Genes affected
PCDHGA4 (HGNC:8702): (protocadherin gamma subfamily A, 4) 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]
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]
PCDHGA2 (HGNC:8700): (protocadherin gamma subfamily A, 2) 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]
PCDHGA3 (HGNC:8701): (protocadherin gamma subfamily A, 3) 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]
PCDHGB1 (HGNC:8708): (protocadherin gamma subfamily B, 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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PCDHGA4 | NM_018917.4 | c.597G>C | p.Gln199His | missense_variant | 1/4 | ENST00000571252.3 | NP_061740.2 | |
| PCDHGA1 | NM_018912.3 | c.2421+22599G>C | intron_variant | ENST00000517417.3 | NP_061735.1 | |||
| PCDHGA2 | NM_018915.4 | c.2424+14309G>C | intron_variant | ENST00000394576.3 | NP_061738.1 | |||
| PCDHGA3 | NM_018916.4 | c.2424+9247G>C | intron_variant | ENST00000253812.8 | NP_061739.2 | |||
| PCDHGB1 | NM_018922.3 | c.2409+3035G>C | intron_variant | ENST00000523390.2 | NP_061745.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PCDHGA4 | ENST00000571252.3 | c.597G>C | p.Gln199His | missense_variant | 1/4 | 1 | NM_018917.4 | ENSP00000458570 | P1 | |
| PCDHGA3 | ENST00000253812.8 | c.2424+9247G>C | intron_variant | 1 | NM_018916.4 | ENSP00000253812 | P1 | |||
| PCDHGA2 | ENST00000394576.3 | c.2424+14309G>C | intron_variant | 1 | NM_018915.4 | ENSP00000378077 | P1 | |||
| PCDHGA1 | ENST00000517417.3 | c.2421+22599G>C | intron_variant | 1 | NM_018912.3 | ENSP00000431083 | P1 | |||
| PCDHGB1 | ENST00000523390.2 | c.2409+3035G>C | intron_variant | 1 | NM_018922.3 | ENSP00000429273 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249146Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135188
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461670Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727118
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GnomAD4 genome
GnomAD4 genome
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33
Bravo
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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 submitter | clinical testing | Ambry Genetics | Nov 18, 2023 | The c.504G>C (p.Q168H) alteration is located in exon 1 (coding exon 1) of the PCDHGA4 gene. This alteration results from a G to C substitution at nucleotide position 504, causing the glutamine (Q) at amino acid position 168 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MutationTaster
Benign
D;D;D;N;D
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at