rs1761296958

Variant names:

• chr5-140786298-T-G
• rs1761296958
• NM_018900.4:c.8T>G

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.8T>G​(p.Phe3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000965 in 1,451,526 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.50
• 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=0.17745838).

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.8T>G	p.Phe3Cys	missense	Exon 1 of 4	NP_061723.1	Q9Y5I3-1
	PCDHA1	NM_031410.3		c.8T>G	p.Phe3Cys	missense	Exon 1 of 1	NP_113598.1	Q9Y5I3-3
	PCDHA1	NM_031411.3		c.8T>G	p.Phe3Cys	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.8T>G	p.Phe3Cys	missense	Exon 1 of 4	ENSP00000420840.3	Q9Y5I3-1
	PCDHA1	ENST00000394633.7	TSL:1	c.8T>G	p.Phe3Cys	missense	Exon 1 of 4	ENSP00000378129.3	Q9Y5I3-2
	PCDHA1	ENST00000378133.4	TSL:6	c.8T>G	p.Phe3Cys	missense	Exon 1 of 1	ENSP00000367373.3	Q9Y5I3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000965 AC: 14 AN: 1451526 Hom.: 0 Cov.: 31 AF XY: 0.00000831 AC XY: 6 AN XY: 721658

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 84796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1107112

Other (OTH) AF: 0.0000334 AC: 2 AN: 59844

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.5
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.035
Sift	Benign	0.087	T
Sift4G	Benign	0.28	T
Polyphen		0.92	P
Vest4		0.11
MutPred		0.39		Gain of catalytic residue at M1 (P = 2e-04)
MVP		0.64
MPC		0.73
ClinPred		0.28	T
GERP RS		1.6
PromoterAI		-0.031	Neutral
Varity_R		0.14
gMVP		0.76
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: rs1761296958; hg19: chr5-140165883;