5-141339744-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_018915.4(PCDHGA2):​c.773G>A​(p.Gly258Asp) 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 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCDHGA2
NM_018915.4 missense

Scores

1
2
15

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.91
Variant links:
Genes affected
PCDHGA2 (HGNC:8700): (protocadherin gamma subfamily A, 2) 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 (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;
BP6
Variant 5-141339744-G-A is Benign according to our data. Variant chr5-141339744-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3415385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PCDHGA2NM_018915.4 linkc.773G>A p.Gly258Asp missense_variant Exon 1 of 4 ENST00000394576.3 NP_061738.1 Q9Y5H1-1
PCDHGA1NM_018912.3 linkc.2421+6639G>A intron_variant Intron 1 of 3 ENST00000517417.3 NP_061735.1 Q9Y5H4-1
PCDHGA2NM_032009.3 linkc.773G>A p.Gly258Asp missense_variant Exon 1 of 1 NP_114398.1 Q9Y5H1-2
PCDHG@ n.141339744G>A intragenic_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCDHGA2ENST00000394576.3 linkc.773G>A p.Gly258Asp missense_variant Exon 1 of 4 1 NM_018915.4 ENSP00000378077.2 Q9Y5H1-1
PCDHGA1ENST00000517417.3 linkc.2421+6639G>A intron_variant Intron 1 of 3 1 NM_018912.3 ENSP00000431083.1 Q9Y5H4-1
PCDHGA2ENST00000528330.2 linkc.773G>A p.Gly258Asp missense_variant Exon 1 of 1 6 ENSP00000483020.1 Q9Y5H1-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461834
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Aug 11, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.14
.;T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.020
T
MetaRNN
Uncertain
0.68
D;D
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.3
M;M
PROVEAN
Pathogenic
-6.7
.;D
REVEL
Benign
0.20
Sift
Benign
0.097
.;T
Sift4G
Benign
0.066
T;T
Polyphen
0.56
P;P
Vest4
0.21
MutPred
0.79
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.70
MPC
1.2
ClinPred
0.74
D
GERP RS
2.2
Varity_R
0.19
gMVP
0.44

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: chr5-140719311; COSMIC: COSV54001042; COSMIC: COSV54001042; API