chr5-141214287-T-C

Position:

• chr5-141214287-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018933.4(PCDHB13):​c.164T>C​(p.Leu55Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,531,280 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PCDHB13 NM_018933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB13	NM_018933.4	c.164T>C	p.Leu55Pro	missense_variant	1/1	ENST00000341948.6	NP_061756.1
PCDHB@		n.141214287T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB13	ENST00000341948.6	c.164T>C	p.Leu55Pro	missense_variant	1/1	6	NM_018933.4	ENSP00000345491.4
ENSG00000280029	ENST00000624192.1	n.72+27386A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000142 AC: 21 AN: 147682 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000170 AC: 33 AN: 194066 Hom.: 0 AF XY: 0.000170 AC XY: 18 AN XY: 105582

Gnomad AFR exome AF: 0.000549

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000165

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 191 AN: 1383598 Hom.: 1 Cov.: 22 AF XY: 0.000145 AC XY: 100 AN XY: 690026

Gnomad4 AFR exome AF: 0.000283

Gnomad4 AMR exome AF: 0.0000935

Gnomad4 ASJ exome AF: 0.0000786

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.0000755

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.000142 AC: 21 AN: 147682 Hom.: 0 Cov.: 28 AF XY: 0.000167 AC XY: 12 AN XY: 71778

Gnomad4 AFR AF: 0.000177

Gnomad4 AMR AF: 0.0000678

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000179

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000936 AC: 11

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

Sep 25, 2023

The c.164T>C (p.L55P) alteration is located in exon 1 (coding exon 1) of the PCDHB13 gene. This alteration results from a T to C substitution at nucleotide position 164, causing the leucine (L) at amino acid position 55 to be replaced by a proline (P). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.83	P
Vest4		0.42
MutPred		0.83		Gain of disorder (P = 0.0382);
MVP		0.58
ClinPred		0.20	T
GERP RS		0.86
Varity_R		0.57
gMVP		0.64

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: rs200174243; hg19: chr5-140593859;