5-140786375-G-C

Position:

• chr5-140786375-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.85G>C​(p.Gly29Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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=0.2249111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.85G>C	p.Gly29Arg	missense_variant	1/4	ENST00000504120.4	NP_061723.1
PCDHA1	NM_031410.2	c.85G>C	p.Gly29Arg	missense_variant	1/1		NP_113598.1
PCDHA1	NM_031411.3	c.85G>C	p.Gly29Arg	missense_variant	1/4		NP_113599.1
PCDHA@		n.140786375G>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.85G>C	p.Gly29Arg	missense_variant	1/4	1	NM_018900.4	ENSP00000420840.3
PCDHA1	ENST00000394633.7	c.85G>C	p.Gly29Arg	missense_variant	1/4	1		ENSP00000378129.3
PCDHA1	ENST00000378133.4	c.85G>C	p.Gly29Arg	missense_variant	1/1	6		ENSP00000367373.3
ENSG00000279726	ENST00000655235.1	n.3137C>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Nov 09, 2024

The c.85G>C (p.G29R) 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 85, causing the glycine (G) at amino acid position 29 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	M;M;M
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.20	B;P;B
Vest4		0.29
MutPred		0.63		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);
MVP		0.55
MPC		0.88
ClinPred		0.88	D
GERP RS		1.8
Varity_R		0.17
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1761302685; hg19: chr5-140165960;