1-17438234-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

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

Scores

1
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.536
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RCC2NM_018715.4 linkc.281G>A p.Arg94His missense_variant Exon 2 of 13 ENST00000375436.9 NP_061185.1 Q9P258A0A024RAC5
RCC2NM_001136204.3 linkc.281G>A p.Arg94His missense_variant Exon 1 of 12 NP_001129676.1 Q9P258A0A024RAC5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RCC2ENST00000375436.9 linkc.281G>A p.Arg94His missense_variant Exon 2 of 13 1 NM_018715.4 ENSP00000364585.4 Q9P258
RCC2ENST00000375433.3 linkc.281G>A p.Arg94His missense_variant Exon 1 of 12 1 ENSP00000364582.3 Q9P258

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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000931
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.281G>A (p.R94H) alteration is located in exon 2 (coding exon 1) of the RCC2 gene. This alteration results from a G to A substitution at nucleotide position 281, causing the arginine (R) at amino acid position 94 to be replaced by a histidine (H). 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
0.35
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.073
T;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;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.088
Sift
Uncertain
0.014
D;D
Sift4G
Uncertain
0.050
T;T
Polyphen
0.97
D;D
Vest4
0.14
MutPred
0.41
Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP
0.20
MPC
1.5
ClinPred
0.61
D
GERP RS
0.88
Varity_R
0.43
gMVP
0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-17764730; API