chr5-141214530-A-G

Position:

• chr5-141214530-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018933.4(PCDHB13):​c.407A>G​(p.Asp136Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,613,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: PCDHB13 NM_018933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.274

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]

PCDHB@ (HGNC:):

ACMG classification

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=0.008165926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB13	NM_018933.4	c.407A>G	p.Asp136Gly	missense_variant	1/1	ENST00000341948.6	NP_061756.1
PCDHB@		n.141214530A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB13	ENST00000341948.6	c.407A>G	p.Asp136Gly	missense_variant	1/1	6	NM_018933.4	ENSP00000345491.4
ENSG00000280029	ENST00000624192.1	n.72+27143T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 151916 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00

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: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 250840 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135730

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000491 AC: 718 AN: 1461792 Hom.: 1 Cov.: 31 AF XY: 0.000510 AC XY: 371 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000610

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151916 Hom.: 0 Cov.: 29 AF XY: 0.000323 AC XY: 24 AN XY: 74192

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000461 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.407A>G (p.D136G) alteration is located in exon 1 (coding exon 1) of the PCDHB13 gene. This alteration results from a A to G substitution at nucleotide position 407, causing the aspartic acid (D) at amino acid position 136 to be replaced by a glycine (G). 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	0.094
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.089	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.029
Sift	Uncertain	0.016	D
Sift4G	Benign	0.20	T
Polyphen		0.068	B
Vest4		0.13
MVP		0.40
ClinPred		0.043	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.24

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

Other links and lift over

dbSNP: rs146535847; hg19: chr5-140594102;