5-141331138-G-C

Variant names:

• chr5-141331138-G-C
• rs2472647
• NM_018912.3:c.454G>C

Variant summary

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

The NM_018912.3(PCDHGA1):​c.454G>C​(p.Val152Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDHGA1 NM_018912.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 25 publications found

Genes affected

PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHG@ (HGNC:8695):

ENSG00000294471 (HGNC:):

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=0.08046919).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018912.3. 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
	PCDHGA1	NM_018912.3	MANE Select	c.454G>C	p.Val152Leu	missense	Exon 1 of 4	NP_061735.1
	PCDHGA1	NM_031993.2		c.454G>C	p.Val152Leu	missense	Exon 1 of 1	NP_114382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHGA1	ENST00000517417.3	TSL:1 MANE Select	c.454G>C	p.Val152Leu	missense	Exon 1 of 4	ENSP00000431083.1
	PCDHGA1	ENST00000378105.4	TSL:6	c.454G>C	p.Val152Leu	missense	Exon 1 of 1	ENSP00000367345.3
	ENSG00000294471	ENST00000723807.1		n.80-102C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.18	N
PhyloP100		1.2
PROVEAN	Benign	0.70	N
REVEL	Benign	0.069
Sift	Benign	0.066	T
Sift4G	Uncertain	0.050	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.58		Gain of catalytic residue at V152 (P = 0.0405)
MVP		0.47
MPC		0.28
ClinPred		0.13	T
GERP RS		0.075
Varity_R		0.072
gMVP		0.043
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2472647; hg19: chr5-140710705;