Genetic Variant PCDHB1:p.Asp128Tyr (chr5-141051852-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_013340.4(PCDHB1):c.382G>T(p.Asp128Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCDHB1
NM_013340.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.04

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 links:

PCDHB@ (HGNC:8679):

PCDHB@ links:

PCDHB1-AS1 (HGNC:56111): (PCDHB1 antisense RNA 1)

PCDHB1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB1	NM_013340.4 link	c.382G>T	p.Asp128Tyr	missense_variant	Exon 1 of 1	ENST00000306549.6	NP_037472.2	Q9Y5F3
PCDHB@		n.141051852G>T		intragenic_variant
PCDHB1-AS1	NR_105056.2 link	n.357-682C>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHB1	ENST00000306549.6 link	c.382G>T	p.Asp128Tyr	missense_variant	Exon 1 of 1	6	NM_013340.4	ENSP00000307234.4	Q9Y5F3
PCDHB1-AS1	ENST00000623741.3 link	n.295-682C>A		intron_variant	Intron 3 of 3	3
PCDHB1-AS1	ENST00000624139.3 link	n.124-682C>A		intron_variant	Intron 1 of 2	3
PCDHB1-AS1	ENST00000624778.1 link	n.350-682C>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382G>T (p.D128Y) alteration is located in exon 1 (coding exon 1) of the PCDHB1 gene. This alteration results from a G to T substitution at nucleotide position 382, causing the aspartic acid (D) at amino acid position 128 to be replaced by a tyrosine (Y). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

4.8

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.8

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.84

Gain of phosphorylation at D128 (P = 0.0612);

MVP

0.83

MPC

1.3

ClinPred

1.0

GERP RS

5.8

Varity_R

0.94

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over