1-17420746-T-A

Variant names:

• chr1-17420746-T-A
• rs750168150
• NM_018715.4:c.827A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018715.4(RCC2):​c.827A>T​(p.Tyr276Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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. Y276C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RCC2 NM_018715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018715.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCC2	NM_018715.4	MANE Select	c.827A>T	p.Tyr276Phe	missense	Exon 7 of 13	NP_061185.1	A0A024RAC5
	RCC2	NM_001136204.3		c.827A>T	p.Tyr276Phe	missense	Exon 6 of 12	NP_001129676.1	Q9P258

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCC2	ENST00000375436.9	TSL:1 MANE Select	c.827A>T	p.Tyr276Phe	missense	Exon 7 of 13	ENSP00000364585.4	Q9P258
	RCC2	ENST00000375433.3	TSL:1	c.827A>T	p.Tyr276Phe	missense	Exon 6 of 12	ENSP00000364582.3	Q9P258
	RCC2	ENST00000927104.1		c.827A>T	p.Tyr276Phe	missense	Exon 6 of 12	ENSP00000597163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456546 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724552

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 43260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 84896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110504

Other (OTH) AF: 0.00 AC: 0 AN: 60180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0105333), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Benign	0.70	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.68
Sift	Benign	0.17	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.72		Gain of ubiquitination at K272 (P = 0.1191)
MVP		0.77
MPC		0.97
ClinPred		0.76	D
GERP RS		5.5
Varity_R		0.45
gMVP		0.66
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750168150; hg19: chr1-17747242;