1-17438391-A-T

Position:

• chr1-17438391-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018715.4(RCC2):​c.124T>A​(p.Cys42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,108,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.560

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075149894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCC2	NM_018715.4	c.124T>A	p.Cys42Ser	missense_variant	2/13	ENST00000375436.9	NP_061185.1
RCC2	NM_001136204.3	c.124T>A	p.Cys42Ser	missense_variant	1/12		NP_001129676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCC2	ENST00000375436.9	c.124T>A	p.Cys42Ser	missense_variant	2/13	1	NM_018715.4	ENSP00000364585	P1
RCC2	ENST00000375433.3	c.124T>A	p.Cys42Ser	missense_variant	1/12	1		ENSP00000364582	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000361 AC: 4 AN: 1108176 Hom.: 0 Cov.: 30 AF XY: 0.00000188 AC XY: 1 AN XY: 532378

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000426

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.124T>A (p.C42S) alteration is located in exon 2 (coding exon 1) of the RCC2 gene. This alteration results from a T to A substitution at nucleotide position 124, causing the cysteine (C) at amino acid position 42 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.019	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.037
Sift	Benign	0.75	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	B;B
Vest4		0.27
MutPred		0.30		Gain of phosphorylation at C42 (P = 4e-04);Gain of phosphorylation at C42 (P = 4e-04);
MVP		0.082
MPC		1.0
ClinPred		0.038	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.10
gMVP		0.14

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: chr1-17764887;