5-140795059-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018905.3(PCDHA2):​c.95G>A​(p.Arg32His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PCDHA2 NM_018905.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06680584).

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>A	p.Arg32His	missense	Exon 1 of 4	NP_061728.1	Q9Y5H9-1
	PCDHA1	NM_018900.4	MANE Select	c.2394+6375G>A		intron	N/A	NP_061723.1	Q9Y5I3-1
	PCDHA2	NM_031495.2		c.95G>A	p.Arg32His	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>A	p.Arg32His	missense	Exon 1 of 4	ENSP00000431748.1	Q9Y5H9-1
	PCDHA2	ENST00000520672.2	TSL:1	c.95G>A	p.Arg32His	missense	Exon 1 of 2	ENSP00000430584.2	Q9Y5H9-3
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.2394+6375G>A		intron	N/A	ENSP00000420840.3	Q9Y5I3-1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250556 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000565

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461538 Hom.: 0 Cov.: 184 AF XY: 0.00000825 AC XY: 6 AN XY: 727082

African (AFR) AF: 0.000418 AC: 14 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: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

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

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74510

African (AFR) AF: 0.000433 AC: 18 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000494 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.82
DANN	Benign	0.89
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.43
PROVEAN	Benign	5.9	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Polyphen		0.0020	B
Vest4		0.082
MutPred		0.69		Loss of phosphorylation at S34 (P = 0.0625)
MVP		0.25
ClinPred		0.011	T
GERP RS		0.85
PromoterAI		-0.033	Neutral
Varity_R		0.029
gMVP		0.59
Mutation Taster		=97/3	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;