rs138877576

Variant names:

• chr5-141339764-A-C
• rs138877576
• NM_018915.4:c.793A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-141339764-A-C
• chr5-141339764-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018915.4(PCDHGA2):​c.793A>C​(p.Thr265Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCDHGA2 NM_018915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.857

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]

PCDHG@ (HGNC:8695):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHGA2	NM_018915.4	c.793A>C	p.Thr265Pro	missense_variant	Exon 1 of 4	ENST00000394576.3	NP_061738.1
PCDHGA1	NM_018912.3	c.2421+6659A>C		intron_variant	Intron 1 of 3	ENST00000517417.3	NP_061735.1
PCDHGA2	NM_032009.3	c.793A>C	p.Thr265Pro	missense_variant	Exon 1 of 1		NP_114398.1
PCDHG@		n.141339764A>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHGA2	ENST00000394576.3	c.793A>C	p.Thr265Pro	missense_variant	Exon 1 of 4	1	NM_018915.4	ENSP00000378077.2
PCDHGA1	ENST00000517417.3	c.2421+6659A>C		intron_variant	Intron 1 of 3	1	NM_018912.3	ENSP00000431083.1
PCDHGA2	ENST00000528330.2	c.793A>C	p.Thr265Pro	missense_variant	Exon 1 of 1	6		ENSP00000483020.1

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	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.047	.;T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.86	D;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M
PROVEAN	Uncertain	-2.6	.;D
REVEL	Benign	0.19
Sift	Benign	0.054	.;T
Sift4G	Benign	0.086	T;D
Polyphen		0.90	P;P
Vest4		0.36
MutPred		0.57		Gain of phosphorylation at T267 (P = 0.1089);Gain of phosphorylation at T267 (P = 0.1089);
MVP		0.46
MPC		1.1
ClinPred		0.83	D
GERP RS		2.8
Varity_R		0.49
gMVP		0.48

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: rs138877576; hg19: chr5-140719331;