17-40294388-C-T

Variant names:

• chr17-40294388-C-T
• rs387906842
• NM_001254.4:c.968C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001254.4(CDC6):​c.968C>T​(p.Thr323Ile) 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. T323R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC6 NM_001254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• Publications: 6 publications found

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]

CDC6 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 5

  Inheritance: Unknown, AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40294388-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30271.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC6	NM_001254.4	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 12	ENST00000209728.9	NP_001245.1
CDC6	XM_011525541.3	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 13		XP_011523843.1
CDC6	XM_011525542.2	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 13		XP_011523844.1
CDC6	XM_047437207.1	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 12		XP_047293163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC6	ENST00000209728.9	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 12	1	NM_001254.4	ENSP00000209728.4
CDC6	ENST00000649662.1	c.968C>T	p.Thr323Ile	missense_variant	Exon 7 of 12			ENSP00000497345.1
CDC6	ENST00000582402.1	n.203-968C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.4	M;M;M
PhyloP100		6.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D;.;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		0.88	P;P;P
Vest4		0.87
MutPred		0.64		Gain of MoRF binding (P = 0.354);Gain of MoRF binding (P = 0.354);Gain of MoRF binding (P = 0.354);
MVP		0.87
MPC		0.78
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906842; hg19: chr17-38450640;