rs973659696

Variant names:

• chr1-17416581-G-A
• rs973659696
• NM_018715.4:c.925C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-17416581-G-A
• chr1-17416581-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018715.4(RCC2):​c.925C>T​(p.Pro309Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P309A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCC2	NM_018715.4	c.925C>T	p.Pro309Ser	missense_variant	Exon 8 of 13	ENST00000375436.9	NP_061185.1
RCC2	NM_001136204.3	c.925C>T	p.Pro309Ser	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.925C>T	p.Pro309Ser	missense_variant	Exon 8 of 13	1	NM_018715.4	ENSP00000364585.4
RCC2	ENST00000375433.3	c.925C>T	p.Pro309Ser	missense_variant	Exon 7 of 12	1		ENSP00000364582.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.67	P;P
Vest4		0.58
MutPred		0.82		Gain of catalytic residue at P309 (P = 0.044);Gain of catalytic residue at P309 (P = 0.044);
MVP		0.88
MPC		1.5
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.80

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

Other links and lift over

dbSNP: rs973659696; hg19: chr1-17743077;