Genetic Variant NM_018932.4:c.613C>A (chr5-141209520-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018932.4(PCDHB12):c.613C>A(p.Arg205Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDHB12
NM_018932.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.276

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:

PCDHB@ (HGNC:8679):

PCDHB@ links:

ENSG00000280029 (HGNC:):

ENSG00000280029 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0685204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB12	NM_018932.4 link	c.613C>A	p.Arg205Ser	missense_variant	Exon 1 of 1	ENST00000239450.4	NP_061755.1	Q9Y5F1-1
PCDHB@		n.141209520C>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHB12	ENST00000239450.4 link	c.613C>A	p.Arg205Ser	missense_variant	Exon 1 of 1	6	NM_018932.4	ENSP00000239450.2	Q9Y5F1-1
PCDHB12	ENST00000624949.1 link	c.-98-301C>A		intron_variant	Intron 1 of 1	2		ENSP00000485303.1	Q9Y5F1-2
PCDHB12	ENST00000622978.1 link	c.166-301C>A		intron_variant	Intron 1 of 1	2		ENSP00000485352.1	A0A096LP27
ENSG00000280029	ENST00000624192.1 link	n.72+32153G>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

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:

0.0000166

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.4

DANN

Benign

0.91

DEOGEN2

Benign

0.0018

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.59

M_CAP

Benign

0.012

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.80

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.64

REVEL

Benign

0.032

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Polyphen

0.0060

Vest4

0.11

MutPred

0.39

Gain of phosphorylation at R205 (P = 0.0452);

MVP

0.21

MPC

0.25

ClinPred

0.11

GERP RS

2.5

Varity_R

0.13

gMVP

0.079

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

Computational scores

Splicing

Publications

Other links and lift over