chr5-141351445-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018922.3(PCDHGB1):ā€‹c.1185G>Cā€‹(p.Lys395Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 33)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

PCDHGB1
NM_018922.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.502
Variant links:
Genes affected
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.041478276).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDHGB1NM_018922.3 linkuse as main transcriptc.1185G>C p.Lys395Asn missense_variant 1/4 ENST00000523390.2
PCDHGA1NM_018912.3 linkuse as main transcriptc.2421+18340G>C intron_variant ENST00000517417.3
PCDHGA2NM_018915.4 linkuse as main transcriptc.2424+10050G>C intron_variant ENST00000394576.3
PCDHGA3NM_018916.4 linkuse as main transcriptc.2424+4988G>C intron_variant ENST00000253812.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDHGB1ENST00000523390.2 linkuse as main transcriptc.1185G>C p.Lys395Asn missense_variant 1/41 NM_018922.3 P1Q9Y5G3-1
PCDHGA3ENST00000253812.8 linkuse as main transcriptc.2424+4988G>C intron_variant 1 NM_018916.4 P1Q9Y5H0-1
PCDHGA2ENST00000394576.3 linkuse as main transcriptc.2424+10050G>C intron_variant 1 NM_018915.4 P1Q9Y5H1-1
PCDHGA1ENST00000517417.3 linkuse as main transcriptc.2421+18340G>C intron_variant 1 NM_018912.3 P1Q9Y5H4-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000203
AC:
5
AN:
246356
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133692
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000449
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1460602
Hom.:
0
Cov.:
33
AF XY:
0.0000206
AC XY:
15
AN XY:
726486
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:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000331
AC:
4

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 GeneticsMay 30, 2024The c.1185G>C (p.K395N) alteration is located in exon 1 (coding exon 1) of the PCDHGB1 gene. This alteration results from a G to C substitution at nucleotide position 1185, causing the lysine (K) at amino acid position 395 to be replaced by an asparagine (N). 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
0.21
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
14
DANN
Benign
0.80
DEOGEN2
Benign
0.023
.;T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.39
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.041
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L
MutationTaster
Benign
0.62
N;N;N;N
PROVEAN
Benign
-1.0
.;N
REVEL
Benign
0.041
Sift
Benign
0.49
.;T
Sift4G
Benign
0.69
T;T
Polyphen
0.016
B;B
Vest4
0.34
MutPred
0.37
Loss of ubiquitination at K395 (P = 0.0127);Loss of ubiquitination at K395 (P = 0.0127);
MVP
0.17
MPC
1.3
ClinPred
0.058
T
GERP RS
1.6
Varity_R
0.071
gMVP
0.045

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: rs566234229; hg19: chr5-140731012; API