5-140786691-G-C

Position:

• chr5-140786691-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018900.4(PCDHA1):​c.401G>C​(p.Arg134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0800

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071962565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.401G>C	p.Arg134Thr	missense_variant	1/4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.401G>C	p.Arg134Thr	missense_variant	1/1		NP_113598.1
PCDHA1	NM_031411.3	c.401G>C	p.Arg134Thr	missense_variant	1/4		NP_113599.1
PCDHA@		n.140786691G>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.401G>C	p.Arg134Thr	missense_variant	1/4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.401G>C	p.Arg134Thr	missense_variant	1/4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.401G>C	p.Arg134Thr	missense_variant	1/1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.2821C>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2023

The c.401G>C (p.R134T) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a G to C substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.031	.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.20	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;N
PROVEAN	Benign	0.82	N;N;N
REVEL	Benign	0.050
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.091	T;D;D
Polyphen		0.062	B;B;B
Vest4		0.20
MutPred		0.42		Gain of phosphorylation at R134 (P = 0.0677);Gain of phosphorylation at R134 (P = 0.0677);Gain of phosphorylation at R134 (P = 0.0677);
MVP		0.23
MPC		0.44
ClinPred		0.077	T
GERP RS		-2.5
Varity_R		0.042
gMVP		0.11

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140166276;