5-141151296-A-T

Variant summary

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

The NM_018939.4(PCDHB6):​c.1039A>T​(p.Met347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

PCDHB6
NM_018939.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.17
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=0.014626116).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDHB6NM_018939.4 linkuse as main transcriptc.1039A>T p.Met347Leu missense_variant 1/1 ENST00000231136.4
PCDHB6NM_001303145.2 linkuse as main transcriptc.631A>T p.Met211Leu missense_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDHB6ENST00000231136.4 linkuse as main transcriptc.1039A>T p.Met347Leu missense_variant 1/1 NM_018939.4 P1
ENST00000624192.1 linkuse as main transcriptn.73-14113T>A intron_variant, non_coding_transcript_variant 5
ENST00000624802.1 linkuse as main transcriptn.364+21137T>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000412
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000290
AC:
73
AN:
251484
Hom.:
1
AF XY:
0.000280
AC XY:
38
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00208
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000352
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000324
AC:
473
AN:
1461894
Hom.:
1
Cov.:
87
AF XY:
0.000305
AC XY:
222
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00207
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000346
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000412
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000499
Hom.:
0
Bravo
AF:
0.000242
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000264
AC:
32
EpiCase
AF:
0.000600
EpiControl
AF:
0.000771

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 05, 2022The c.1039A>T (p.M347L) alteration is located in exon 1 (coding exon 1) of the PCDHB6 gene. This alteration results from a A to T substitution at nucleotide position 1039, causing the methionine (M) at amino acid position 347 to be replaced by a leucine (L). 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
0.096
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
0.24
DANN
Benign
0.48
DEOGEN2
Benign
0.013
.;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.56
.;T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.015
T;T
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.56
N;.
REVEL
Benign
0.024
Sift
Benign
0.38
T;.
Sift4G
Benign
0.52
T;T
Vest4
0.15
MutPred
0.44
Loss of catalytic residue at M347 (P = 0.0412);.;
MVP
0.055
ClinPred
0.020
T
GERP RS
-3.0
gMVP
0.058

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: rs147390258; hg19: chr5-140530877; API