5-140786313-G-T

Variant names:

• chr5-140786313-G-T
• rs782547817
• NM_018900.4:c.23G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018900.4(PCDHA1):​c.23G>T​(p.Gly8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. G8D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.505
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19856852).

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.23G>T	p.Gly8Val	missense	Exon 1 of 4	NP_061723.1	Q9Y5I3-1
	PCDHA1	NM_031410.3		c.23G>T	p.Gly8Val	missense	Exon 1 of 1	NP_113598.1	Q9Y5I3-3
	PCDHA1	NM_031411.3		c.23G>T	p.Gly8Val	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.23G>T	p.Gly8Val	missense	Exon 1 of 4	ENSP00000420840.3	Q9Y5I3-1
	PCDHA1	ENST00000394633.7	TSL:1	c.23G>T	p.Gly8Val	missense	Exon 1 of 4	ENSP00000378129.3	Q9Y5I3-2
	PCDHA1	ENST00000378133.4	TSL:6	c.23G>T	p.Gly8Val	missense	Exon 1 of 1	ENSP00000367373.3	Q9Y5I3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458054 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725148

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109990

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.48
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.51
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.079
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.91	P
Vest4		0.38
MutPred		0.54		Loss of sheet (P = 0.0037)
MVP		0.65
MPC		0.65
ClinPred		0.60	D
GERP RS		0.49
PromoterAI		-0.026	Neutral
Varity_R		0.081
gMVP		0.59
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: rs782547817; hg19: chr5-140165898;