chr5-141339012-T-G

Variant names:

• chr5-141339012-T-G
• rs747009936
• NM_018915.4:c.41T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018915.4(PCDHGA2):​c.41T>G​(p.Val14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PCDHGA2 NM_018915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.410

Genes affected

PCDHGA2 (HGNC:8700): (protocadherin gamma subfamily A, 2) 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]

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):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28803897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHGA2	NM_018915.4	c.41T>G	p.Val14Gly	missense_variant	Exon 1 of 4	ENST00000394576.3	NP_061738.1
PCDHGA1	NM_018912.3	c.2421+5907T>G		intron_variant	Intron 1 of 3	ENST00000517417.3	NP_061735.1
PCDHGA2	NM_032009.3	c.41T>G	p.Val14Gly	missense_variant	Exon 1 of 1		NP_114398.1
PCDHG@		n.141339012T>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHGA2	ENST00000394576.3	c.41T>G	p.Val14Gly	missense_variant	Exon 1 of 4	1	NM_018915.4	ENSP00000378077.2
PCDHGA1	ENST00000517417.3	c.2421+5907T>G		intron_variant	Intron 1 of 3	1	NM_018912.3	ENSP00000431083.1
PCDHGA2	ENST00000528330.2	c.41T>G	p.Val14Gly	missense_variant	Exon 1 of 1	6		ENSP00000483020.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235348 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430434 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M;M
PROVEAN	Pathogenic	-5.9	.;D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	.;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.11	B;B
Vest4		0.43
MutPred		0.57		Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);
MVP		0.61
MPC		0.60
ClinPred		0.33	T
GERP RS		2.6
Varity_R		0.25
gMVP		0.32

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: rs747009936; hg19: chr5-140718579;