rs2472647

Positions:

• chr5-141331138-G-A
• chr5-141331138-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.96 (69968 hom., cov: 32)
  • Exomes 𝑓: 0.97 (688005 hom.)
• Consequence: PCDHGA1 NM_018912.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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]

PCDHG@ (HGNC:):

ACMG classification

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	c.454G>A	p.Val152Ile	missense_variant	1/4	ENST00000517417.3	NP_061735.1
PCDHGA1	NM_031993.2	c.454G>A	p.Val152Ile	missense_variant	1/1		NP_114382.1
PCDHG@		n.141331138G>A		intragenic_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145813 AN: 152200 Hom.: 69914 Cov.: 32

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

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.: 67 AF XY: 0.970 AC XY: 705265 AN XY: 727228

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.: 32 AF XY: 0.958 AC XY: 71323 AN XY: 74476

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	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.048	.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	7.3e-7	T;T
MetaSVM	Benign	-1.0	T
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	T
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

Other links and lift over

dbSNP: rs2472647; hg19: chr5-140710705;