Variant chr5-141150667-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001303145.2(PCDHB6):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

PCDHB6
NM_001303145.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.16

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:

PCDHB@ (HGNC:):

PCDHB@ links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB6	NM_018939.4 linkuse as main transcript	c.410T>C	p.Met137Thr	missense_variant	1/1	ENST00000231136.4	NP_061762.2	Q9Y5E3
PCDHB6	NM_001303145.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/2		NP_001290074.1	Q9Y5E3B4DSB6A0A096LNH7
PCDHB@	use as main transcript	n.141150667T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB6	ENST00000231136.4 linkuse as main transcript	c.410T>C	p.Met137Thr	missense_variant	1/1	6	NM_018939.4	ENSP00000231136.1		Q9Y5E3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

250478

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000422

AC:

617

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

284

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000206

Gnomad4 NFE exome

AF:

0.000521

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000184

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000310

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

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

Jun 12, 2023

The c.410T>C (p.M137T) alteration is located in exon 1 (coding exon 1) of the PCDHB6 gene. This alteration results from a T to C substitution at nucleotide position 410, causing the methionine (M) at amino acid position 137 to be replaced by a threonine (T). 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

0.27

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.071

.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

D;.

REVEL

Benign

0.17

Sift

Benign

0.053

T;.

Sift4G

Benign

0.10

T;D

Vest4

0.42

MVP

0.29

ClinPred

0.10

GERP RS

4.8

gMVP

0.26

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