5-141331377-G-T

Variant summary

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

The NM_018912.3(PCDHGA1):​c.693G>T​(p.Gln231His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 6.8e-7 ( 0 hom. )

Consequence

PCDHGA1
NM_018912.3 missense

Scores

2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.647
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]

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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=0.147906).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDHGA1NM_018912.3 linkc.693G>T p.Gln231His missense_variant Exon 1 of 4 ENST00000517417.3 NP_061735.1 Q9Y5H4-1
PCDHGA1NM_031993.2 linkc.693G>T p.Gln231His missense_variant Exon 1 of 1 NP_114382.1 Q9Y5H4-2
PCDHG@ n.141331377G>T intragenic_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDHGA1ENST00000517417.3 linkc.693G>T p.Gln231His missense_variant Exon 1 of 4 1 NM_018912.3 ENSP00000431083.1 Q9Y5H4-1
PCDHGA1ENST00000378105.4 linkc.693G>T p.Gln231His missense_variant Exon 1 of 1 6 ENSP00000367345.3 Q9Y5H4-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461872
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.058
.;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.47
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.065
N;N
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.064
Sift
Uncertain
0.018
D;D
Sift4G
Uncertain
0.029
D;T
Polyphen
0.70
P;P
Vest4
0.28
MutPred
0.38
Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);
MVP
0.44
MPC
0.78
ClinPred
0.48
T
GERP RS
1.2
Varity_R
0.084
gMVP
0.090

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.

Other links and lift over

hg19: chr5-140710944; API