Genetic Variant RGCC:p.Ser29Trp (chr13-41458321-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014059.3(RGCC):c.86C>G(p.Ser29Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,584,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

RGCC
NM_014059.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

RGCC (HGNC:20369): (regulator of cell cycle) This gene is thought to regulate cell cycle progression. It is induced by p53 in response to DNA damage, or by sublytic levels of complement system proteins that result in activation of the cell cycle. The encoded protein localizes to the cytoplasm during interphase and to centrosomes during mitosis. The protein forms a complex with polo-like kinase 1. The protein also translocates to the nucleus in response to treatment with complement system proteins, and can associate with and increase the kinase activity of cell division cycle 2 protein. In different assays and cell types, overexpression of this protein has been shown to activate or suppress cell cycle progression. [provided by RefSeq, Jul 2008]

RGCC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20625442).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGCC	NM_014059.3 link	c.86C>G	p.Ser29Trp	missense_variant	Exon 2 of 5	ENST00000379359.4	NP_054778.2	Q9H4X1-1
RGCC	XM_047430282.1 link	c.86C>G	p.Ser29Trp	missense_variant	Exon 2 of 3		XP_047286238.1
RGCC	XR_007063677.1 link	n.244C>G		non_coding_transcript_exon_variant	Exon 2 of 4
RGCC	XR_941565.2 link	n.244C>G		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGCC	ENST00000379359.4 link	c.86C>G	p.Ser29Trp	missense_variant	Exon 2 of 5	1	NM_014059.3	ENSP00000368664.3		Q9H4X1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

202210

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

112054

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000128

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000768

AC:

AN:

1432454

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

711598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000471

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000772

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.86C>G (p.S29W) alteration is located in exon 2 (coding exon 2) of the RGCC gene. This alteration results from a C to G substitution at nucleotide position 86, causing the serine (S) at amino acid position 29 to be replaced by a tryptophan (W). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.056

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.020

Polyphen

0.91

Vest4

0.26

MutPred

0.30

Loss of disorder (P = 0.0037);

MVP

0.21

MPC

1.4

ClinPred

0.78

GERP RS

4.5

Varity_R

0.50

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over