chr5-140795332-T-G

Variant names:

• chr5-140795332-T-G
• rs370073139
• NM_018905.3:c.368T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018905.3(PCDHA2):​c.368T>G​(p.Val123Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCDHA2 NM_018905.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.95

Genes affected

PCDHA2 (HGNC:8668): (protocadherin alpha 2) 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 (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]

ENSG00000279726 (HGNC:):

PCDHA@ (HGNC:8662):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA2	NM_018905.3	c.368T>G	p.Val123Gly	missense_variant	Exon 1 of 4	ENST00000526136.2	NP_061728.1
PCDHA1	NM_018900.4	c.2394+6648T>G		intron_variant	Intron 1 of 3	ENST00000504120.4	NP_061723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA2	ENST00000526136.2	c.368T>G	p.Val123Gly	missense_variant	Exon 1 of 4	1	NM_018905.3	ENSP00000431748.1
PCDHA1	ENST00000504120.4	c.2394+6648T>G		intron_variant	Intron 1 of 3	1	NM_018900.4	ENSP00000420840.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.8	H;H;H
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.59
MutPred		0.64		Loss of stability (P = 0.0024);Loss of stability (P = 0.0024);Loss of stability (P = 0.0024);
MVP		0.83
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.87
gMVP		0.71

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

Other links and lift over

dbSNP: rs370073139; hg19: chr5-140174917;