Variant chr5-141151296-A-T details in Genebe, Genetics Data Aggregator

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

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]

PCDHB6 links:

(HGNC:):

links:

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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=0.014626116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB6	NM_018939.4 linkuse as main transcript	c.1039A>T	p.Met347Leu	missense_variant	1/1	ENST00000231136.4
PCDHB6	NM_001303145.2 linkuse as main transcript	c.631A>T	p.Met211Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PCDHB6	ENST00000231136.4 linkuse as main transcript	c.1039A>T	p.Met347Leu	missense_variant	1/1		NM_018939.4	P1
	ENST00000624192.1 linkuse as main transcript	n.73-14113T>A		intron_variant, non_coding_transcript_variant		5
	ENST00000624802.1 linkuse as main transcript	n.364+21137T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152074

Hom.:

Cov.:

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:

AN:

251484

Hom.:

AF XY:

0.000280

AC XY:

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.:

Cov.:

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:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

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.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

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 submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The 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

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

LIST_S2

Benign

0.56

.;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over