chr6-33293257-C-G

Variant names:

• chr6-33293257-C-G
• rs114812653
• NM_004761.5:c.1766G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004761.5(RGL2):​c.1766G>C​(p.Ser589Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,547,910 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (8 hom.)
• Consequence: RGL2 NM_004761.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.70

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029233098).
• BP6: Variant 6-33293257-C-G is Benign according to our data. Variant chr6-33293257-C-G is described in ClinVar as [Benign]. Clinvar id is 784072.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (894/152356) while in subpopulation AFR AF= 0.0208 (865/41588). AF 95% confidence interval is 0.0196. There are 12 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL2	NM_004761.5	c.1766G>C	p.Ser589Thr	missense_variant	Exon 16 of 18	ENST00000497454.6	NP_004752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGL2	ENST00000497454.6	c.1766G>C	p.Ser589Thr	missense_variant	Exon 16 of 18	1	NM_004761.5	ENSP00000420211.1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152238 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00169 AC: 323 AN: 191644 Hom.: 3 AF XY: 0.00120 AC XY: 122 AN XY: 101532

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.000396

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: 0.0000112

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000484 AC: 676 AN: 1395554 Hom.: 8 Cov.: 34 AF XY: 0.000395 AC XY: 272 AN XY: 687818

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.000540

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: 0.00000278

Gnomad4 OTH exome AF: 0.000853

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152356 Hom.: 12 Cov.: 32 AF XY: 0.00574 AC XY: 428 AN XY: 74502

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00114 Hom.: 3

Bravo AF: 0.00691

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 233

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.65	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.049
Sift	Benign	0.68	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.33
MPC		0.32
ClinPred		0.014	T
GERP RS		3.6
Varity_R		0.071
gMVP		0.35

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: rs114812653; hg19: chr6-33261034;