chr6-33293189-G-A

Variant names:

• chr6-33293189-G-A
• rs762460397
• NM_004761.5:c.1834C>T

Variant summary

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

The NM_004761.5(RGL2):​c.1834C>T​(p.Arg612*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,441,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: RGL2 NM_004761.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004761.5. 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
	RGL2	NM_004761.5	MANE Select	c.1834C>T	p.Arg612*	stop_gained	Exon 16 of 18	NP_004752.1	A0A024RCS9
	RGL2	NM_001243738.2		c.1588C>T	p.Arg530*	stop_gained	Exon 15 of 17	NP_001230667.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL2	ENST00000497454.6	TSL:1 MANE Select	c.1834C>T	p.Arg612*	stop_gained	Exon 16 of 18	ENSP00000420211.1	O15211-1
	RGL2	ENST00000437840.6	TSL:1	n.1739C>T		non_coding_transcript_exon	Exon 15 of 17
	RGL2	ENST00000968840.1		c.1894C>T	p.Arg632*	stop_gained	Exon 16 of 18	ENSP00000638899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000443 AC: 1 AN: 225984 AF XY: 0.00000822

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1441664 Hom.: 0 Cov.: 33 AF XY: 0.00000419 AC XY: 3 AN XY: 716034

African (AFR) AF: 0.00 AC: 0 AN: 32988

American (AMR) AF: 0.00 AC: 0 AN: 42036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24290

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102806

Other (OTH) AF: 0.00 AC: 0 AN: 59506

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		1.6
Vest4		0.91
GERP RS		2.6
Mutation Taster		=96/104	disease causing (fs/PTC)

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: rs762460397; hg19: chr6-33260966;