Variant 5-141209016-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018932.4(PCDHB12):c.109G>A(p.Glu37Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,456,292 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: 0.000019 ( 0 hom. )

Consequence

PCDHB12
NM_018932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.45

Variant links:

Genes affected

PCDHB12 (HGNC:8683): (protocadherin beta 12) 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]

PCDHB12 links:

(HGNC:):

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB12	NM_018932.4 linkuse as main transcript	c.109G>A	p.Glu37Lys	missense_variant	1/1	ENST00000239450.4	NP_061755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB12	ENST00000239450.4 linkuse as main transcript	c.109G>A	p.Glu37Lys	missense_variant	1/1		NM_018932.4	ENSP00000239450	P1	Q9Y5F1-1
	ENST00000624192.1 linkuse as main transcript	n.72+32657C>T		intron_variant, non_coding_transcript_variant		5
PCDHB12	ENST00000622978.1 linkuse as main transcript	c.109G>A	p.Glu37Lys	missense_variant	1/2	2		ENSP00000485352
PCDHB12	ENST00000624949.1 linkuse as main transcript	c.-99+74G>A		intron_variant		2		ENSP00000485303		Q9Y5F1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1456292

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

724226

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

The c.109G>A (p.E37K) alteration is located in exon 1 (coding exon 1) of the PCDHB12 gene. This alteration results from a G to A substitution at nucleotide position 109, causing the glutamic acid (E) at amino acid position 37 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

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

.;T

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

4.4

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

.;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.85

MutPred

0.91

Gain of ubiquitination at E37 (P = 0.0192);Gain of ubiquitination at E37 (P = 0.0192);

MVP

0.88

MPC

0.80

ClinPred

1.0

GERP RS

4.2

Varity_R

0.66

gMVP

0.96

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

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