1-17438319-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018715.4(RCC2):​c.196G>T​(p.Gly66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000887 in 1,239,958 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G66D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

RCC2
NM_018715.4 missense

Scores

2
3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.026974052).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RCC2NM_018715.4 linkc.196G>T p.Gly66Cys missense_variant Exon 2 of 13 ENST00000375436.9 NP_061185.1 Q9P258A0A024RAC5
RCC2NM_001136204.3 linkc.196G>T p.Gly66Cys 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.196G>T p.Gly66Cys missense_variant Exon 2 of 13 1 NM_018715.4 ENSP00000364585.4 Q9P258
RCC2ENST00000375433.3 linkc.196G>T p.Gly66Cys missense_variant Exon 1 of 12 1 ENSP00000364582.3 Q9P258

Frequencies

GnomAD3 genomes
AF:
0.0000201
AC:
3
AN:
149460
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000583
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000734
AC:
8
AN:
1090498
Hom.:
0
Cov.:
30
AF XY:
0.00000567
AC XY:
3
AN XY:
528852
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000132
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000250
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000485
GnomAD4 genome
AF:
0.0000201
AC:
3
AN:
149460
Hom.:
0
Cov.:
32
AF XY:
0.0000412
AC XY:
3
AN XY:
72890
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000583
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.0000633
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 05, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.196G>T (p.G66C) alteration is located in exon 2 (coding exon 1) of the RCC2 gene. This alteration results from a G to T substitution at nucleotide position 196, causing the glycine (G) at amino acid position 66 to be replaced by a cysteine (C). 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
Benign
0.13
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.049
T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.11
N
M_CAP
Pathogenic
0.47
D
MetaRNN
Benign
0.027
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.34
N;N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.68
N;N
REVEL
Benign
0.085
Sift
Uncertain
0.022
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
0.99
D;D
Vest4
0.28
MutPred
0.36
Gain of methylation at K67 (P = 0.0259);Gain of methylation at K67 (P = 0.0259);
MVP
0.13
MPC
0.91
ClinPred
0.63
D
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.20
gMVP
0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749681186; hg19: chr1-17764815; API