chr1-17438234-C-T

Variant names:

• chr1-17438234-C-T
• NM_018715.4:c.281G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_018715.4(RCC2):​c.281G>A​(p.Arg94His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,159,490 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.536
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16659251).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.281G>A	p.Arg94His	missense	Exon 2 of 13	NP_061185.1	A0A024RAC5
	RCC2	NM_001136204.3		c.281G>A	p.Arg94His	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.281G>A	p.Arg94His	missense	Exon 2 of 13	ENSP00000364585.4	Q9P258
	RCC2	ENST00000375433.3	TSL:1	c.281G>A	p.Arg94His	missense	Exon 1 of 12	ENSP00000364582.3	Q9P258
	RCC2	ENST00000927104.1		c.281G>A	p.Arg94His	missense	Exon 1 of 12	ENSP00000597163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000431 AC: 5 AN: 1159490 Hom.: 0 Cov.: 30 AF XY: 0.00000697 AC XY: 4 AN XY: 573624

African (AFR) AF: 0.00 AC: 0 AN: 22768

American (AMR) AF: 0.00 AC: 0 AN: 21580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15340

East Asian (EAS) AF: 0.00 AC: 0 AN: 19478

South Asian (SAS) AF: 0.0000931 AC: 5 AN: 53716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2824

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 943584

Other (OTH) AF: 0.00 AC: 0 AN: 42624

GnomAD4 genome Cov.: 32

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.067	N
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.54
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.088
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.050	T
Polyphen		0.97	D
Vest4		0.14
MutPred		0.41		Gain of loop (P = 0.0312)
MVP		0.20
MPC		1.5
ClinPred		0.61	D
GERP RS		0.88
PromoterAI		0.070	Neutral
Varity_R		0.43
gMVP		0.25
Mutation Taster		=86/14	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

hg19: chr1-17764730;