1-165891293-C-G

Variant names:

• chr1-165891293-C-G
• rs538874834
• NM_012474.5:c.327C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012474.5(UCK2):​c.327C>G​(p.Ile109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UCK2 NM_012474.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.805
• Publications: 0 publications found

Genes affected

UCK2 (HGNC:12562): (uridine-cytidine kinase 2) This gene encodes a pyrimidine ribonucleoside kinase. The encoded protein (EC 2.7.1.48) catalyzes phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively.[provided by RefSeq, Oct 2010]

ENSG00000236364 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012474.5. 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
	UCK2	NM_012474.5	MANE Select	c.327C>G	p.Ile109Met	missense	Exon 3 of 7	NP_036606.2
	UCK2	NM_001363568.2		c.264C>G	p.Ile88Met	missense	Exon 4 of 8	NP_001350497.1	A0A2R8Y653

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCK2	ENST00000367879.9	TSL:1 MANE Select	c.327C>G	p.Ile109Met	missense	Exon 3 of 7	ENSP00000356853.4	Q9BZX2-1
	UCK2	ENST00000642653.1		c.264C>G	p.Ile88Met	missense	Exon 4 of 8	ENSP00000494961.1	A0A2R8Y653
	UCK2	ENST00000940421.1		c.327C>G	p.Ile109Met	missense	Exon 3 of 5	ENSP00000610480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727244

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.81
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.49
MutPred		0.45		Gain of disorder (P = 0.0969)
MVP		0.41
MPC		1.8
ClinPred		0.97	D
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.85
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs538874834; hg19: chr1-165860530; COSMIC: COSV63316254; COSMIC: COSV63316254;