5-140788566-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000504120.4(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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDHA1 ENST00000504120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62
• Publications: 34 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000504120.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA1	NM_018900.4	MANE Select	c.2276G>C	p.Cys759Ser	missense	Exon 1 of 4	NP_061723.1
	PCDHA1	NM_031410.3		c.2276G>C	p.Cys759Ser	missense	Exon 1 of 1	NP_113598.1
	PCDHA1	NM_031411.3		c.1602+674G>C		intron	N/A	NP_113599.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.2276G>C	p.Cys759Ser	missense	Exon 1 of 4	ENSP00000420840.3
	ENSG00000279726	ENST00000624712.1	TSL:1	n.944C>G		non_coding_transcript_exon	Exon 2 of 2
	PCDHA1	ENST00000394633.7	TSL:1	c.1602+674G>C		intron	N/A	ENSP00000378129.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		4.6
PROVEAN	Pathogenic	-7.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.26	B
Vest4		0.48
MutPred		0.37		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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2240695; hg19: chr5-140168151;