5-140786787-C-T

Variant names:

• chr5-140786787-C-T
• rs781919950
• NM_018900.4:c.497C>T

Variant summary

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

The NM_018900.4(PCDHA1):​c.497C>T​(p.Ala166Val) variant causes a missense change. 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: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13

Genes affected

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 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
PCDHA1	NM_018900.4	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 1		NP_113598.1
PCDHA1	NM_031411.3	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 4		NP_113599.1
PCDHA@		n.140786787C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.497C>T	p.Ala166Val	missense_variant	Exon 1 of 1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.2725G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M;M;M
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.23
MutPred		0.79		Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP		0.63
MPC		0.81
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.18

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: rs781919950; hg19: chr5-140166372;