5-140795059-G-C

Variant names:

• chr5-140795059-G-C
• rs563648142
• NM_018905.3:c.95G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018905.3(PCDHA2):​c.95G>C​(p.Arg32Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDHA2 NM_018905.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018905.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA2	NM_018905.3	MANE Select	c.95G>C	p.Arg32Pro	missense	Exon 1 of 4	NP_061728.1	Q9Y5H9-1
	PCDHA1	NM_018900.4	MANE Select	c.2394+6375G>C		intron	N/A	NP_061723.1	Q9Y5I3-1
	PCDHA2	NM_031495.2		c.95G>C	p.Arg32Pro	missense	Exon 1 of 1	NP_113683.1	Q9Y5H9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA2	ENST00000526136.2	TSL:1 MANE Select	c.95G>C	p.Arg32Pro	missense	Exon 1 of 4	ENSP00000431748.1	Q9Y5H9-1
	PCDHA2	ENST00000520672.2	TSL:1	c.95G>C	p.Arg32Pro	missense	Exon 1 of 2	ENSP00000430584.2	Q9Y5H9-3
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.2394+6375G>C		intron	N/A	ENSP00000420840.3	Q9Y5I3-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461536 Hom.: 0 Cov.: 184 AF XY: 0.00000275 AC XY: 2 AN XY: 727080

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.0000482 AC: 2 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.43
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.044	D
Polyphen		0.12	B
Vest4		0.48
MutPred		0.73		Loss of catalytic residue at R32 (P = 0.0415)
MVP		0.51
ClinPred		0.26	T
GERP RS		0.85
PromoterAI		-0.054	Neutral
Varity_R		0.83
gMVP		0.94
Mutation Taster		=95/5	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: rs563648142; hg19: chr5-140174644;