5-141375258-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018919.3(PCDHGA6):​c.1175T>C​(p.Phe392Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PCDHGA6
NM_018919.3 missense

Scores

11
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21
Variant links:
Genes affected
PCDHGA6 (HGNC:8704): (protocadherin gamma subfamily A, 6) 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]
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]
PCDHGA5 (HGNC:8703): (protocadherin gamma subfamily A, 5) 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]
PCDHGB2 (HGNC:8709): (protocadherin gamma subfamily B, 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]
PCDHGB3 (HGNC:8710): (protocadherin gamma subfamily B, 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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDHGA6NM_018919.3 linkuse as main transcriptc.1175T>C p.Phe392Ser missense_variant 1/4 ENST00000517434.3 NP_061742.1
PCDHGA1NM_018912.3 linkuse as main transcriptc.2421+42153T>C intron_variant ENST00000517417.3 NP_061735.1
PCDHGA2NM_018915.4 linkuse as main transcriptc.2424+33863T>C intron_variant ENST00000394576.3 NP_061738.1
PCDHGA3NM_018916.4 linkuse as main transcriptc.2424+28801T>C intron_variant ENST00000253812.8 NP_061739.2
PCDHGA4NM_018917.4 linkuse as main transcriptc.2514+17637T>C intron_variant ENST00000571252.3 NP_061740.2
PCDHGA5NM_018918.3 linkuse as main transcriptc.2421+8507T>C intron_variant ENST00000518069.2 NP_061741.1
PCDHGB1NM_018922.3 linkuse as main transcriptc.2409+22589T>C intron_variant ENST00000523390.2 NP_061745.1
PCDHGB2NM_018923.3 linkuse as main transcriptc.2421+12702T>C intron_variant ENST00000522605.2 NP_061746.1
PCDHGB3NM_018924.5 linkuse as main transcriptc.2415+2449T>C intron_variant ENST00000576222.2 NP_061747.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDHGA6ENST00000517434.3 linkuse as main transcriptc.1175T>C p.Phe392Ser missense_variant 1/41 NM_018919.3 ENSP00000429601 P1Q9Y5G7-1
PCDHGA3ENST00000253812.8 linkuse as main transcriptc.2424+28801T>C intron_variant 1 NM_018916.4 ENSP00000253812 P1Q9Y5H0-1
PCDHGA2ENST00000394576.3 linkuse as main transcriptc.2424+33863T>C intron_variant 1 NM_018915.4 ENSP00000378077 P1Q9Y5H1-1
PCDHGA1ENST00000517417.3 linkuse as main transcriptc.2421+42153T>C intron_variant 1 NM_018912.3 ENSP00000431083 P1Q9Y5H4-1
PCDHGA5ENST00000518069.2 linkuse as main transcriptc.2421+8507T>C intron_variant 1 NM_018918.3 ENSP00000429834 P1Q9Y5G8-1
PCDHGB2ENST00000522605.2 linkuse as main transcriptc.2421+12702T>C intron_variant 1 NM_018923.3 ENSP00000429018 P1Q9Y5G2-1
PCDHGB1ENST00000523390.2 linkuse as main transcriptc.2409+22589T>C intron_variant 1 NM_018922.3 ENSP00000429273 P1Q9Y5G3-1
PCDHGA4ENST00000571252.3 linkuse as main transcriptc.2514+17637T>C intron_variant 1 NM_018917.4 ENSP00000458570 P1Q9Y5G9-1
PCDHGB3ENST00000576222.2 linkuse as main transcriptc.2415+2449T>C intron_variant 1 NM_018924.5 ENSP00000461862 P1Q9Y5G1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

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 GeneticsJun 10, 2024The c.1175T>C (p.F392S) alteration is located in exon 1 (coding exon 1) of the PCDHGA6 gene. This alteration results from a T to C substitution at nucleotide position 1175, causing the phenylalanine (F) at amino acid position 392 to be replaced by a serine (S). 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.84
T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Pathogenic
4.9
H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PROVEAN
Pathogenic
-8.0
D;.
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.79
Gain of disorder (P = 4e-04);Gain of disorder (P = 4e-04);
MVP
0.93
MPC
1.3
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.91
gMVP
0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140754825; API