5-141150933-G-A

Variant summary

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

The NM_018939.4(PCDHB6):​c.676G>A​(p.Glu226Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDHB6
NM_018939.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.759
Variant links:
Genes affected
PCDHB6 (HGNC:8691): (protocadherin beta 6) 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. Unlike the alpha and gamma clusters, the transcripts from these genes do not share common 3' exons. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell neural connections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Genome browser will be placed here

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=0.047881424).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDHB6NM_018939.4 linkuse as main transcriptc.676G>A p.Glu226Lys missense_variant 1/1 ENST00000231136.4
PCDHB6NM_001303145.2 linkuse as main transcriptc.268G>A p.Glu90Lys missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDHB6ENST00000231136.4 linkuse as main transcriptc.676G>A p.Glu226Lys missense_variant 1/1 NM_018939.4 P1
ENST00000624192.1 linkuse as main transcriptn.73-13750C>T intron_variant, non_coding_transcript_variant 5
ENST00000624802.1 linkuse as main transcriptn.364+21500C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461884
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 GeneticsJan 31, 2022The c.676G>A (p.E226K) alteration is located in exon 1 (coding exon 1) of the PCDHB6 gene. This alteration results from a G to A substitution at nucleotide position 676, causing the glutamic acid (E) at amino acid position 226 to be replaced by a lysine (K). 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
0.077
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
9.5
DANN
Benign
0.83
DEOGEN2
Benign
0.0077
.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.066
N
LIST_S2
Benign
0.18
.;T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.048
T;T
MetaSVM
Benign
-0.90
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.52
N;.
REVEL
Benign
0.013
Sift
Benign
0.80
T;.
Sift4G
Benign
0.62
T;T
Vest4
0.12
MutPred
0.33
Gain of ubiquitination at E226 (P = 0.0128);.;
MVP
0.28
ClinPred
0.028
T
GERP RS
-3.6
gMVP
0.25

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: rs1752840533; hg19: chr5-140530514; COSMIC: COSV50700578; API