Genetic Variant PCDHA1:p.Cys759Phe (chr5-140788566-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018900.4(PCDHA1):c.2276G>T(p.Cys759Phe) variant causes a missense change. The variant allele was found at a frequency of 0.527 in 1,613,562 control chromosomes in the GnomAD database, including 224,522 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.51 ( 20263 hom., cov: 33)

Exomes 𝑓: 0.53 ( 204259 hom. )

Consequence

PCDHA1
NM_018900.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.62

Variant links:

Genes affected

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 links:

ENSG00000279726 (HGNC:):

ENSG00000279726 links:

PCDHA@ (HGNC:8662):

PCDHA@ links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.6917458E-4).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4 link	c.2276G>T	p.Cys759Phe	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1	Q9Y5I3-1
PCDHA1	NM_031410.2 link	c.2276G>T	p.Cys759Phe	missense_variant	Exon 1 of 1		NP_113598.1	Q9Y5I3-3
PCDHA1	NM_031411.3 link	c.1602+674G>T		intron_variant	Intron 1 of 3		NP_113599.1	Q9Y5I3-2
PCDHA@		n.140788566G>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4 link	c.2276G>T	p.Cys759Phe	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3		Q9Y5I3-1

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

78076

AN:

151896

Hom.:

20246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.484

Gnomad AMI

AF:

0.789

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.523

Gnomad EAS

AF:

0.522

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.460

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.523

GnomAD3 exomes

AF:

0.525

AC:

131704

AN:

250672

Hom.:

34807

AF XY:

0.527

AC XY:

71412

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.483

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.525

Gnomad EAS exome

AF:

0.539

Gnomad SAS exome

AF:

0.544

Gnomad FIN exome

AF:

0.452

Gnomad NFE exome

AF:

0.530

Gnomad OTH exome

AF:

0.526

GnomAD4 exome

AF:

0.528

AC:

771891

AN:

1461548

Hom.:

204259

Cov.:

AF XY:

0.529

AC XY:

384783

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.483

Gnomad4 AMR exome

AF:

0.553

Gnomad4 ASJ exome

AF:

0.525

Gnomad4 EAS exome

AF:

0.500

Gnomad4 SAS exome

AF:

0.550

Gnomad4 FIN exome

AF:

0.455

Gnomad4 NFE exome

AF:

0.531

Gnomad4 OTH exome

AF:

0.528

GnomAD4 genome

AF:

0.514

AC:

78128

AN:

152014

Hom.:

20263

Cov.:

AF XY:

0.512

AC XY:

38036

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.484

Gnomad4 AMR

AF:

0.530

Gnomad4 ASJ

AF:

0.523

Gnomad4 EAS

AF:

0.522

Gnomad4 SAS

AF:

0.536

Gnomad4 FIN

AF:

0.460

Gnomad4 NFE

AF:

0.530

Gnomad4 OTH

AF:

0.519

Alfa

AF:

0.507

Hom.:

8439

Bravo

AF:

0.523

TwinsUK

AF:

0.535

AC:

1985

ALSPAC

AF:

0.532

AC:

2051

ESP6500AA

AF:

0.493

AC:

2172

ESP6500EA

AF:

0.528

AC:

4540

ExAC

AF:

0.524

AC:

63630

Asia WGS

AF:

0.454

AC:

1579

AN:

3478

EpiCase

AF:

0.546

EpiControl

AF:

0.548

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.48

.;T

Eigen

Benign

0.052

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.00027

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.5

M;M

PROVEAN

Pathogenic

-8.2

D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.17

B;B

Vest4

0.43

MPC

0.54

ClinPred

0.087

GERP RS

4.3

Varity_R

0.70

gMVP

0.43

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over