1-17416566-T-C

Variant names:

• chr1-17416566-T-C
• NM_018715.4:c.940A>G

Variant summary

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

The NM_018715.4(RCC2):​c.940A>G​(p.Ile314Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,730 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: 0.0000014 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

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=0.18097141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCC2	NM_018715.4	c.940A>G	p.Ile314Val	missense_variant	Exon 8 of 13	ENST00000375436.9	NP_061185.1
RCC2	NM_001136204.3	c.940A>G	p.Ile314Val	missense_variant	Exon 7 of 12		NP_001129676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCC2	ENST00000375436.9	c.940A>G	p.Ile314Val	missense_variant	Exon 8 of 13	1	NM_018715.4	ENSP00000364585.4
RCC2	ENST00000375433.3	c.940A>G	p.Ile314Val	missense_variant	Exon 7 of 12	1		ENSP00000364582.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

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: 0.00000180

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

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.940A>G (p.I314V) alteration is located in exon 8 (coding exon 7) of the RCC2 gene. This alteration results from a A to G substitution at nucleotide position 940, causing the isoleucine (I) at amino acid position 314 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.31	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.0	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.36	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.061	B;B
Vest4		0.21
MutPred		0.43		Loss of stability (P = 0.0505);Loss of stability (P = 0.0505);
MVP		0.44
MPC		0.73
ClinPred		0.75	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.17
gMVP		0.43

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: chr1-17743062;