5-140786774-A-G

Variant names:

• chr5-140786774-A-G
• rs1761331289
• NM_018900.4:c.484A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018900.4(PCDHA1):​c.484A>G​(p.Ile162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. I162L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058850527).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018900.4. 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
	PCDHA1	NM_018900.4	MANE Select	c.484A>G	p.Ile162Val	missense	Exon 1 of 4	NP_061723.1	Q9Y5I3-1
	PCDHA1	NM_031410.3		c.484A>G	p.Ile162Val	missense	Exon 1 of 1	NP_113598.1	Q9Y5I3-3
	PCDHA1	NM_031411.3		c.484A>G	p.Ile162Val	missense	Exon 1 of 4	NP_113599.1	Q9Y5I3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.484A>G	p.Ile162Val	missense	Exon 1 of 4	ENSP00000420840.3	Q9Y5I3-1
	PCDHA1	ENST00000394633.7	TSL:1	c.484A>G	p.Ile162Val	missense	Exon 1 of 4	ENSP00000378129.3	Q9Y5I3-2
	PCDHA1	ENST00000378133.4	TSL:6	c.484A>G	p.Ile162Val	missense	Exon 1 of 1	ENSP00000367373.3	Q9Y5I3-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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 Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.51
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.095	N
PhyloP100		0.017
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.075
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.038	B
Vest4		0.035
MutPred		0.57		Loss of catalytic residue at L167 (P = 0.0706)
MVP		0.34
MPC		0.26
ClinPred		0.062	T
GERP RS		3.0
PromoterAI		0.017	Neutral
Varity_R		0.024
gMVP		0.048
Mutation Taster		=100/0	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: rs1761331289; hg19: chr5-140166359;