5-141052240-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_013340.4(PCDHB1):​c.770A>G​(p.Asn257Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PCDHB1
NM_013340.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.19
Variant links:
Genes affected
PCDHB1 (HGNC:8680): (protocadherin beta 1) This gene is a member of the protocadherin beta gene cluster, one of three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily. The extracellular domains interact in a homophilic manner to specify differential cell-cell connections. Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3' exons as expected. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins. Their specific functions are unknown but they most likely play a critical role in the establishment and function of specific cell-cell neural connections. [provided by RefSeq, Jul 2008]
PCDHB1-AS1 (HGNC:56111): (PCDHB1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity PCDB1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033831596).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDHB1NM_013340.4 linkc.770A>G p.Asn257Ser missense_variant Exon 1 of 1 ENST00000306549.6 NP_037472.2 Q9Y5F3
PCDHB@ n.141052240A>G intragenic_variant
PCDHB1-AS1NR_105056.2 linkn.357-1070T>C intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDHB1ENST00000306549.6 linkc.770A>G p.Asn257Ser missense_variant Exon 1 of 1 6 NM_013340.4 ENSP00000307234.4 Q9Y5F3
PCDHB1-AS1ENST00000623741.3 linkn.295-1070T>C intron_variant Intron 3 of 3 3
PCDHB1-AS1ENST00000624139.3 linkn.124-1070T>C intron_variant Intron 1 of 2 3
PCDHB1-AS1ENST00000624778.1 linkn.350-1070T>C intron_variant Intron 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251242
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461878
Hom.:
0
Cov.:
33
AF XY:
0.0000179
AC XY:
13
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000497
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152100
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000825
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
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
Jul 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.770A>G (p.N257S) alteration is located in exon 1 (coding exon 1) of the PCDHB1 gene. This alteration results from a A to G substitution at nucleotide position 770, causing the asparagine (N) at amino acid position 257 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
Benign
0.066
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
8.8
DANN
Benign
0.27
DEOGEN2
Benign
0.00090
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.73
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.47
N
REVEL
Benign
0.019
Sift
Benign
0.63
T
Sift4G
Benign
0.72
T
Polyphen
0.025
B
Vest4
0.087
MutPred
0.35
Gain of glycosylation at N257 (P = 0.0121);
MVP
0.23
MPC
0.30
ClinPred
0.033
T
GERP RS
-3.3
Varity_R
0.040
gMVP
0.15

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: rs781965896; hg19: chr5-140431825; API