Variant rs2472647 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018912.3(PCDHGA1):c.454G>A(p.Val152Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,614,178 control chromosomes in the GnomAD database, including 757,973 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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 0.96 ( 69968 hom., cov: 32)

Exomes 𝑓: 0.97 ( 688005 hom. )

Consequence

PCDHGA1
NM_018912.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA1 links:

PCDHG@ (HGNC:8695):

PCDHG@ 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=7.3067906E-7).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHGA1	NM_018912.3 link	c.454G>A	p.Val152Ile	missense_variant	1/4	ENST00000517417.3	NP_061735.1	Q9Y5H4-1
PCDHGA1	NM_031993.2 link	c.454G>A	p.Val152Ile	missense_variant	1/1		NP_114382.1	Q9Y5H4-2
PCDHG@		n.141331138G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHGA1	ENST00000517417.3 link	c.454G>A	p.Val152Ile	missense_variant	1/4	1	NM_018912.3	ENSP00000431083.1		Q9Y5H4-1
PCDHGA1	ENST00000378105.4 link	c.454G>A	p.Val152Ile	missense_variant	1/1	6		ENSP00000367345.3		Q9Y5H4-2

Frequencies

GnomAD3 genomes

AF:

0.958

AC:

145813

AN:

152200

Hom.:

69914

Cov.:

show subpopulations

Gnomad AFR

AF:

0.928

Gnomad AMI

AF:

0.912

Gnomad AMR

AF:

0.977

Gnomad ASJ

AF:

0.984

Gnomad EAS

AF:

0.877

Gnomad SAS

AF:

0.952

Gnomad FIN

AF:

0.977

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.975

Gnomad OTH

AF:

0.957

GnomAD3 exomes

AF:

0.963

AC:

241995

AN:

251214

Hom.:

116673

AF XY:

0.964

AC XY:

131012

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.920

Gnomad AMR exome

AF:

0.980

Gnomad ASJ exome

AF:

0.985

Gnomad EAS exome

AF:

0.885

Gnomad SAS exome

AF:

0.956

Gnomad FIN exome

AF:

0.976

Gnomad NFE exome

AF:

0.975

Gnomad OTH exome

AF:

0.963

GnomAD4 exome

AF:

0.970

AC:

1417724

AN:

1461860

Hom.:

688005

Cov.:

AF XY:

0.970

AC XY:

705265

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.922

Gnomad4 AMR exome

AF:

0.981

Gnomad4 ASJ exome

AF:

0.985

Gnomad4 EAS exome

AF:

0.837

Gnomad4 SAS exome

AF:

0.959

Gnomad4 FIN exome

AF:

0.976

Gnomad4 NFE exome

AF:

0.976

Gnomad4 OTH exome

AF:

0.965

GnomAD4 genome

AF:

0.958

AC:

145923

AN:

152318

Hom.:

69968

Cov.:

AF XY:

0.958

AC XY:

71323

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.928

Gnomad4 AMR

AF:

0.977

Gnomad4 ASJ

AF:

0.984

Gnomad4 EAS

AF:

0.877

Gnomad4 SAS

AF:

0.952

Gnomad4 FIN

AF:

0.977

Gnomad4 NFE

AF:

0.975

Gnomad4 OTH

AF:

0.955

Alfa

AF:

0.969

Hom.:

150109

Bravo

AF:

0.956

TwinsUK

AF:

0.974

AC:

3612

ALSPAC

AF:

0.977

AC:

3764

ESP6500AA

AF:

0.921

AC:

4056

ESP6500EA

AF:

0.975

AC:

8385

ExAC

AF:

0.961

AC:

116631

Asia WGS

AF:

0.911

AC:

3168

AN:

3478

EpiCase

AF:

0.974

EpiControl

AF:

0.977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.048

.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.32

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.54

N;N

PROVEAN

Benign

0.84

N;N

REVEL

Benign

0.080

Sift

Benign

0.12

T;T

Sift4G

Benign

0.077

T;T

Polyphen

0.0

B;B

Vest4

0.018

MPC

0.23

ClinPred

0.0024

GERP RS

0.075

Varity_R

0.032

gMVP

0.022

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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