5-141214339-C-G

Position:

chr5-141214339-C-G

Variant summary

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

The NM_018933.4(PCDHB13):c.216C>G(p.Asn72Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000592 in 1,402,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

PCDHB13
NM_018933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -10.3

Variant links:

Genes affected

PCDHB13 (HGNC:8684): (protocadherin beta 13) 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]

PCDHB13 links:

PCDHB@ (HGNC:):

PCDHB@ links:

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=0.043191314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB13	NM_018933.4 linkuse as main transcript	c.216C>G	p.Asn72Lys	missense_variant	1/1	ENST00000341948.6	NP_061756.1	Q9Y5F0
PCDHB@	use as main transcript	n.141214339C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB13	ENST00000341948.6 linkuse as main transcript	c.216C>G	p.Asn72Lys	missense_variant	1/1	6	NM_018933.4	ENSP00000345491.4		Q9Y5F0
ENSG00000280029	ENST00000624192.1 linkuse as main transcript	n.72+27334G>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000109

AC:

AN:

146820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000773

AC:

AN:

168136

Hom.:

AF XY:

0.0000986

AC XY:

AN XY:

91260

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.000129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000873

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1255456

Hom.:

Cov.:

AF XY:

0.0000573

AC XY:

AN XY:

628482

show subpopulations

Gnomad4 AFR exome

AF:

0.000517

Gnomad4 AMR exome

AF:

0.000132

Gnomad4 ASJ exome

AF:

0.000291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000362

Gnomad4 OTH exome

AF:

0.0000941

GnomAD4 genome

AF:

0.000109

AC:

AN:

146820

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

71244

show subpopulations

Gnomad4 AFR

AF:

0.000357

Gnomad4 AMR

AF:

0.000137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000263

AC:

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

Dec 21, 2022

The c.216C>G (p.N72K) alteration is located in exon 1 (coding exon 1) of the PCDHB13 gene. This alteration results from a C to G substitution at nucleotide position 216, causing the asparagine (N) at amino acid position 72 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

Benign

0.17

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.90

DANN

Benign

0.88

DEOGEN2

Benign

0.028

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.12

M_CAP

Benign

0.0054

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.71

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.0080

Sift

Benign

0.13

Sift4G

Benign

0.58

Polyphen

0.030

Vest4

0.10

MutPred

0.45

Gain of MoRF binding (P = 0.0553);

MVP

0.18

ClinPred

0.045

GERP RS

-3.0

Varity_R

0.15

gMVP

0.13

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