1-17438423-G-A

Position:

• chr1-17438423-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018715.4(RCC2):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000534 in 1,124,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000053 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14316124).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCC2	NM_018715.4	c.92C>T	p.Pro31Leu	missense_variant	2/13	ENST00000375436.9	NP_061185.1
RCC2	NM_001136204.3	c.92C>T	p.Pro31Leu	missense_variant	1/12		NP_001129676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCC2	ENST00000375436.9	c.92C>T	p.Pro31Leu	missense_variant	2/13	1	NM_018715.4	ENSP00000364585	P1
RCC2	ENST00000375433.3	c.92C>T	p.Pro31Leu	missense_variant	1/12	1		ENSP00000364582	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000534 AC: 6 AN: 1124504 Hom.: 0 Cov.: 30 AF XY: 0.00000740 AC XY: 4 AN XY: 540380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000313

Gnomad4 FIN exome AF: 0.0000419

Gnomad4 NFE exome AF: 0.00000317

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

Jan 16, 2024

The c.92C>T (p.P31L) alteration is located in exon 2 (coding exon 1) of the RCC2 gene. This alteration results from a C to T substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.099	N
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.88	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.023
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.059	T;T
Polyphen		0.30	B;B
Vest4		0.21
MutPred		0.28		Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);
MVP		0.043
MPC		0.87
ClinPred		0.69	D
GERP RS		1.0
Varity_R		0.060
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: chr1-17764919;