1-17438277-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018715.4(RCC2):​c.238G>T​(p.Gly80Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,307,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21795449).
• BS2: High AC in GnomAd4 at 6 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.238G>T	p.Gly80Cys	missense	Exon 2 of 13	NP_061185.1	A0A024RAC5
	RCC2	NM_001136204.3		c.238G>T	p.Gly80Cys	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>T	p.Gly80Cys	missense	Exon 2 of 13	ENSP00000364585.4	Q9P258
	RCC2	ENST00000375433.3	TSL:1	c.238G>T	p.Gly80Cys	missense	Exon 1 of 12	ENSP00000364582.3	Q9P258
	RCC2	ENST00000927104.1		c.238G>T	p.Gly80Cys	missense	Exon 1 of 12	ENSP00000597163.1

Frequencies

GnomAD3 genomes AF: 0.0000404 AC: 6 AN: 148614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000880

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000450

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000722 AC: 8 AN: 110792 AF XY: 0.0000779

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.000543

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000606

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 53 AN: 1158414 Hom.: 1 Cov.: 30 AF XY: 0.0000560 AC XY: 32 AN XY: 571566

African (AFR) AF: 0.00 AC: 0 AN: 22938

American (AMR) AF: 0.0000972 AC: 2 AN: 20574

Ashkenazi Jewish (ASJ) AF: 0.00186 AC: 29 AN: 15624

East Asian (EAS) AF: 0.00 AC: 0 AN: 19220

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: 0.0000191 AC: 18 AN: 944826

Other (OTH) AF: 0.0000931 AC: 4 AN: 42958

GnomAD4 genome AF: 0.0000404 AC: 6 AN: 148614 Hom.: 0 Cov.: 32 AF XY: 0.0000415 AC XY: 3 AN XY: 72362

African (AFR) AF: 0.00 AC: 0 AN: 41046

American (AMR) AF: 0.00 AC: 0 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 3 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000450 AC: 3 AN: 66614

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000606 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000540 AC: 6

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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.032	N
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.80
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.096
Sift	Benign	0.086	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.31
MutPred		0.47		Gain of sheet (P = 0.0101)
MVP		0.11
MPC		0.91
ClinPred		0.31	T
GERP RS		1.6
PromoterAI		-0.0088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.14
gMVP		0.30
Mutation Taster		=99/1	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;