13-41466919-C-A

Variant names:

• chr13-41466919-C-A
• rs2043852331
• NM_014059.3:c.332C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014059.3(RGCC):​c.332C>A​(p.Thr111Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RGCC NM_014059.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2453731).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014059.3. 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
	RGCC	NM_014059.3	MANE Select	c.332C>A	p.Thr111Asn	missense	Exon 3 of 5	NP_054778.2	Q9H4X1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGCC	ENST00000379359.4	TSL:1 MANE Select	c.332C>A	p.Thr111Asn	missense	Exon 3 of 5	ENSP00000368664.3	Q9H4X1-1
	RGCC	ENST00000888696.1		c.383C>A	p.Thr128Asn	missense	Exon 3 of 5	ENSP00000558755.1
	RGCC	ENST00000888694.1		c.326C>A	p.Thr109Asn	missense	Exon 3 of 5	ENSP00000558753.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459766 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726316

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110128

Other (OTH) AF: 0.00 AC: 0 AN: 60312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.037	D
Polyphen		0.96	D
Vest4		0.13
MutPred		0.17		Loss of phosphorylation at T111 (P = 0.0177)
MVP		0.36
MPC		0.96
ClinPred		0.74	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.11
Mutation Taster		=80/20	polymorphism

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: rs2043852331; hg19: chr13-42041055;