6-33292149-G-A

Variant names:

• chr6-33292149-G-A
• NM_004761.5:c.2287C>T

Variant summary

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

The NM_004761.5(RGL2):​c.2287C>T​(p.Pro763Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGL2 NM_004761.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27777934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL2	NM_004761.5	c.2287C>T	p.Pro763Ser	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.2287C>T	p.Pro763Ser	missense_variant	Exon 18 of 18	1	NM_004761.5	ENSP00000420211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2287C>T (p.P763S) alteration is located in exon 18 (coding exon 17) of the RGL2 gene. This alteration results from a C to T substitution at nucleotide position 2287, causing the proline (P) at amino acid position 763 to be replaced by a serine (S). 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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.042
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.11	B
Vest4		0.55
MutPred		0.29		Gain of phosphorylation at P763 (P = 0.0207);
MVP		0.50
MPC		1.1
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33259926;