1-17438277-C-G

Variant names:

• chr1-17438277-C-G
• rs763666560
• NM_018715.4:c.238G>C

Variant summary

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

The NM_018715.4(RCC2):​c.238G>C​(p.Gly80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000863 in 1,158,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.800
• Publications: 0 publications found

Genes affected

RCC2 (HGNC:30297): (regulator of chromosome condensation 2) The protein encoded by this gene is a guanine exchange factor that is active on RalA, a small GTPase. The encoded protein and RalA are both essential for proper kinetochore-microtubule function in early mitosis. This protein has been shown to be a biomarker for colorectal cancer. [provided by RefSeq, Oct 2016]

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=0.24360272).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018715.4. 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
	RCC2	NM_018715.4	MANE Select	c.238G>C	p.Gly80Arg	missense	Exon 2 of 13	NP_061185.1	A0A024RAC5
	RCC2	NM_001136204.3		c.238G>C	p.Gly80Arg	missense	Exon 1 of 12	NP_001129676.1	Q9P258

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCC2	ENST00000375436.9	TSL:1 MANE Select	c.238G>C	p.Gly80Arg	missense	Exon 2 of 13	ENSP00000364585.4	Q9P258
	RCC2	ENST00000375433.3	TSL:1	c.238G>C	p.Gly80Arg	missense	Exon 1 of 12	ENSP00000364582.3	Q9P258
	RCC2	ENST00000927104.1		c.238G>C	p.Gly80Arg	missense	Exon 1 of 12	ENSP00000597163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.63e-7 AC: 1 AN: 1158418 Hom.: 0 Cov.: 30 AF XY: 0.00000175 AC XY: 1 AN XY: 571570

⚠️ 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: 22938

American (AMR) AF: 0.00 AC: 0 AN: 20574

Ashkenazi Jewish (ASJ) AF: 0.0000640 AC: 1 AN: 15624

East Asian (EAS) AF: 0.00 AC: 0 AN: 19222

South Asian (SAS) AF: 0.00 AC: 0 AN: 52246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2958

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 944828

Other (OTH) AF: 0.00 AC: 0 AN: 42958

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.033	N
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.80
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.062
Sift	Benign	0.52	T
Sift4G	Benign	0.55	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.39		Gain of MoRF binding (P = 0.0093)
MVP		0.14
MPC		1.0
ClinPred		0.36	T
GERP RS		1.6
PromoterAI		0.029	Neutral
Varity_R		0.046
gMVP		0.26
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763666560; hg19: chr1-17764773;