chr17-40289534-T-G

Position:

• chr17-40289534-T-G

Variant summary

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

The NM_001254.4(CDC6):​c.114T>G​(p.Asn38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDC6 NM_001254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900

Genes affected

CDC6 (HGNC:1744): (cell division cycle 6) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cyle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cyle is regulated through its phosphorylation by Cdks. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC6	NM_001254.4	c.114T>G	p.Asn38Lys	missense_variant	2/12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3	c.114T>G	p.Asn38Lys	missense_variant	2/13		XP_011523843.1
CDC6	XM_011525542.2	c.114T>G	p.Asn38Lys	missense_variant	2/13		XP_011523844.1
CDC6	XM_047437207.1	c.114T>G	p.Asn38Lys	missense_variant	2/12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9	c.114T>G	p.Asn38Lys	missense_variant	2/12	1	NM_001254.4	ENSP00000209728	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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 04, 2024

The c.114T>G (p.N38K) alteration is located in exon 2 (coding exon 1) of the CDC6 gene. This alteration results from a T to G substitution at nucleotide position 114, causing the asparagine (N) at amino acid position 38 to be replaced by a lysine (K). 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	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.8
DANN	Benign	0.59
DEOGEN2	Benign	0.010	T;T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.43	.;.;T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.065	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L;L;.;.;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.060	N;.;.;.;.;.
REVEL	Benign	0.031
Sift	Benign	0.31	T;.;.;.;.;.
Sift4G	Benign	0.93	T;.;T;T;.;T
Polyphen		0.0	B;B;.;.;B;.
Vest4		0.12
MutPred		0.21		Gain of ubiquitination at N38 (P = 9e-04);Gain of ubiquitination at N38 (P = 9e-04);Gain of ubiquitination at N38 (P = 9e-04);Gain of ubiquitination at N38 (P = 9e-04);Gain of ubiquitination at N38 (P = 9e-04);Gain of ubiquitination at N38 (P = 9e-04);
MVP		0.47
MPC		0.22
ClinPred		0.25	T
GERP RS		0.27
Varity_R		0.059
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 0

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: chr17-38445786;