5-140786774-A-C

Position:

chr5-140786774-A-C

Variant summary

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

The NM_018900.4(PCDHA1):c.484A>C(p.Ile162Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCDHA1
NM_018900.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0170

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:

Genome browser will be placed here

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=0.19187832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/4	ENST00000504120.4	NP_061723.1	Q9Y5I3-1
PCDHA1	NM_031410.2 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/1		NP_113598.1	Q9Y5I3-3
PCDHA1	NM_031411.3 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/4		NP_113599.1	Q9Y5I3-2
PCDHA@	use as main transcript	n.140786774A>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCDHA1	ENST00000504120.4 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/4	1	NM_018900.4	ENSP00000420840.3	Q9Y5I3-1
PCDHA1	ENST00000394633.7 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/4	1		ENSP00000378129.3	Q9Y5I3-2
PCDHA1	ENST00000378133.4 linkuse as main transcript	c.484A>C	p.Ile162Leu	missense_variant	1/1	6		ENSP00000367373.3	Q9Y5I3-3
ENSG00000279726	ENST00000655235.1 linkuse as main transcript	n.2738T>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Bravo

AF:

0.00000756

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

Aug 04, 2023

The c.484A>C (p.I162L) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a A to C substitution at nucleotide position 484, causing the isoleucine (I) at amino acid position 162 to be replaced by a leucine (L). 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

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;L;L

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.062

Sift

Benign

0.037

D;T;T

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.68

P;B;B

Vest4

0.21

MutPred

0.47

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.54

MPC

0.43

ClinPred

0.52

GERP RS

3.0

Varity_R

0.10

gMVP

0.069

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