6-33292196-G-T

Variant names:

• chr6-33292196-G-T
• rs748649212
• NM_004761.5:c.2240C>A

Variant summary

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

The NM_004761.5(RGL2):​c.2240C>A​(p.Pro747Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RGL2 NM_004761.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

Genes affected

RGL2 (HGNC:9769): (ral guanine nucleotide dissociation stimulator like 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. Predicted to act upstream of or within negative regulation of cardiac muscle cell apoptotic process; positive regulation of phosphatidylinositol 3-kinase signaling; and regulation of Ral protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PFDN6 (HGNC:4926): (prefoldin subunit 6) PFDN6 is a subunit of the heteromeric prefoldin complex that chaperones nascent actin (see MIM 102560) and alpha- and beta-tubulin (see MIM 602529 and MIM 191130, respectively) chains pending their transfer to the cytosolic chaperonin containing TCP1 (MIM 186980) (CCT) complex (Hansen et al., 1999 [PubMed 10209023]).[supplied by OMIM, Jul 2010]

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=0.2088154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL2	NM_004761.5	c.2240C>A	p.Pro747Gln	missense_variant	Exon 18 of 18	ENST00000497454.6	NP_004752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGL2	ENST00000497454.6	c.2240C>A	p.Pro747Gln	missense_variant	Exon 18 of 18	1	NM_004761.5	ENSP00000420211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251416 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.078
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.96	P
Vest4		0.20
MutPred		0.16		Loss of glycosylation at P747 (P = 0.0754);
MVP		0.54
MPC		1.1
ClinPred		0.55	D
GERP RS		4.8
Varity_R		0.077
gMVP		0.50

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: rs748649212; hg19: chr6-33259973;