chr5-140786802-C-G

Variant names:

• chr5-140786802-C-G
• rs1554117547
• NM_018900.4:c.512C>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.512C>G​(p.Thr171Arg) 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. 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)
• Consequence: PCDHA1 NM_018900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.79
• 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=0.02731499).

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.512C>G	p.Thr171Arg	missense	Exon 1 of 4	NP_061723.1	Q9Y5I3-1
	PCDHA1	NM_031410.3		c.512C>G	p.Thr171Arg	missense	Exon 1 of 1	NP_113598.1	Q9Y5I3-3
	PCDHA1	NM_031411.3		c.512C>G	p.Thr171Arg	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.512C>G	p.Thr171Arg	missense	Exon 1 of 4	ENSP00000420840.3	Q9Y5I3-1
	PCDHA1	ENST00000394633.7	TSL:1	c.512C>G	p.Thr171Arg	missense	Exon 1 of 4	ENSP00000378129.3	Q9Y5I3-2
	PCDHA1	ENST00000378133.4	TSL:6	c.512C>G	p.Thr171Arg	missense	Exon 1 of 1	ENSP00000367373.3	Q9Y5I3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.059
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.40
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.050	N
PhyloP100		-1.8
PROVEAN	Benign	2.9	N
REVEL	Benign	0.058
Sift	Benign	0.89	T
Sift4G	Benign	0.98	T
Polyphen		0.0040	B
Vest4		0.14
MutPred		0.44		Gain of phosphorylation at S173 (P = 0.0698)
MVP		0.30
MPC		0.34
ClinPred		0.039	T
GERP RS		0.85
Varity_R		0.091
gMVP		0.22
Mutation Taster		=98/2	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: rs1554117547; hg19: chr5-140166387;