1-17409147-A-T

Position:

• chr1-17409147-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018715.4(RCC2):​c.1512T>A​(p.Ser504Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04879564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCC2	NM_018715.4	c.1512T>A	p.Ser504Arg	missense_variant	13/13	ENST00000375436.9	NP_061185.1
RCC2	NM_001136204.3	c.1512T>A	p.Ser504Arg	missense_variant	12/12		NP_001129676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCC2	ENST00000375436.9	c.1512T>A	p.Ser504Arg	missense_variant	13/13	1	NM_018715.4	ENSP00000364585	P1
RCC2	ENST00000375433.3	c.1512T>A	p.Ser504Arg	missense_variant	12/12	1		ENSP00000364582	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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 18, 2023

The c.1512T>A (p.S504R) alteration is located in exon 13 (coding exon 12) of the RCC2 gene. This alteration results from a T to A substitution at nucleotide position 1512, causing the serine (S) at amino acid position 504 to be replaced by an arginine (R). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.69	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.10
Sift	Benign	0.25	T;T
Sift4G	Benign	0.076	T;T
Polyphen		0.34	B;B
Vest4		0.15
MutPred		0.27		Loss of phosphorylation at S504 (P = 0.0059);Loss of phosphorylation at S504 (P = 0.0059);
MVP		0.15
MPC		1.4
ClinPred		0.27	T
GERP RS		-9.6
Varity_R		0.44
gMVP		0.73

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: chr1-17735643;