5-140788566-G-C

Variant names:

• chr5-140788566-G-C
• rs2240695
• NM_018900.4:c.2276G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018900.4(PCDHA1):​c.2276G>C​(p.Cys759Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C759F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40703285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.2276G>C	p.Cys759Ser	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.2276G>C	p.Cys759Ser	missense_variant	Exon 1 of 1		NP_113598.1
PCDHA1	NM_031411.3	c.1602+674G>C		intron_variant	Intron 1 of 3		NP_113599.1
PCDHA@		n.140788566G>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.2276G>C	p.Cys759Ser	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 59 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.46	.;T
Eigen	Benign	0.048
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.5	M;M
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.26	B;B
Vest4		0.48
MutPred		0.37		Gain of phosphorylation at C759 (P = 0.0087);Gain of phosphorylation at C759 (P = 0.0087);
MVP		0.61
MPC		0.45
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.53
gMVP		0.46

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: rs2240695; hg19: chr5-140168151;