5-141360331-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000522605.2(PCDHGB2):ā€‹c.196C>Gā€‹(p.Leu66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,952 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00053 ( 0 hom., cov: 33)
Exomes š‘“: 0.0014 ( 5 hom. )

Consequence

PCDHGB2
ENST00000522605.2 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47
Variant links:
Genes affected
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]
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]
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13386059).
BS2
High Homozygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDHGB2NM_018923.3 linkuse as main transcriptc.196C>G p.Leu66Val missense_variant 1/4 ENST00000522605.2 NP_061746.1
PCDHGA1NM_018912.3 linkuse as main transcriptc.2421+27226C>G intron_variant ENST00000517417.3 NP_061735.1
PCDHGA2NM_018915.4 linkuse as main transcriptc.2424+18936C>G intron_variant ENST00000394576.3 NP_061738.1
PCDHGA3NM_018916.4 linkuse as main transcriptc.2424+13874C>G intron_variant ENST00000253812.8 NP_061739.2
PCDHGA4NM_018917.4 linkuse as main transcriptc.2514+2710C>G intron_variant ENST00000571252.3 NP_061740.2
PCDHGB1NM_018922.3 linkuse as main transcriptc.2409+7662C>G intron_variant ENST00000523390.2 NP_061745.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDHGB2ENST00000522605.2 linkuse as main transcriptc.196C>G p.Leu66Val missense_variant 1/41 NM_018923.3 ENSP00000429018 P1Q9Y5G2-1
PCDHGA3ENST00000253812.8 linkuse as main transcriptc.2424+13874C>G intron_variant 1 NM_018916.4 ENSP00000253812 P1Q9Y5H0-1
PCDHGA2ENST00000394576.3 linkuse as main transcriptc.2424+18936C>G intron_variant 1 NM_018915.4 ENSP00000378077 P1Q9Y5H1-1
PCDHGA1ENST00000517417.3 linkuse as main transcriptc.2421+27226C>G intron_variant 1 NM_018912.3 ENSP00000431083 P1Q9Y5H4-1
PCDHGB1ENST00000523390.2 linkuse as main transcriptc.2409+7662C>G intron_variant 1 NM_018922.3 ENSP00000429273 P1Q9Y5G3-1
PCDHGA4ENST00000571252.3 linkuse as main transcriptc.2514+2710C>G intron_variant 1 NM_018917.4 ENSP00000458570 P1Q9Y5G9-1

Frequencies

GnomAD3 genomes
AF:
0.000526
AC:
80
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000453
AC:
113
AN:
249214
Hom.:
0
AF XY:
0.000436
AC XY:
59
AN XY:
135212
show subpopulations
Gnomad AFR exome
AF:
0.0000647
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000912
Gnomad OTH exome
AF:
0.000661
GnomAD4 exome
AF:
0.00139
AC:
2035
AN:
1461696
Hom.:
5
Cov.:
32
AF XY:
0.00132
AC XY:
958
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.00169
Gnomad4 OTH exome
AF:
0.00225
GnomAD4 genome
AF:
0.000525
AC:
80
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.000416
AC XY:
31
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00117
Hom.:
0
Bravo
AF:
0.000604
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000272
AC:
1
ESP6500EA
AF:
0.00123
AC:
10
ExAC
AF:
0.000381
AC:
46
EpiCase
AF:
0.00164
EpiControl
AF:
0.00136

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 GeneticsJul 28, 2021The c.196C>G (p.L66V) alteration is located in exon 1 (coding exon 1) of the PCDHGB2 gene. This alteration results from a C to G substitution at nucleotide position 196, causing the leucine (L) at amino acid position 66 to be replaced by a valine (V). 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
0.19
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.0080
.;T
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.9
L;L
MutationTaster
Benign
1.0
D;D;D;D;D;N
PROVEAN
Benign
-2.2
.;N
REVEL
Benign
0.17
Sift
Benign
0.45
.;T
Sift4G
Benign
0.60
T;T
Polyphen
0.92
P;P
Vest4
0.43
MVP
0.47
ClinPred
0.042
T
GERP RS
4.2
Varity_R
0.49
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs146919505; hg19: chr5-140739898; API