rs1130199

Variant names:

• chr17-40291317-T-C
• rs1130199
• NM_001254.4:c.438T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001254.4(CDC6):​c.438T>C​(p.Cys146Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,116 control chromosomes in the GnomAD database, including 4,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (2456 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (2121 hom.)
• Consequence: CDC6 NM_001254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.340
• Publications: 7 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-40291317-T-C is Benign according to our data. Variant chr17-40291317-T-C is described in ClinVar as Benign. ClinVar VariationId is 128636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001254.4. 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
	CDC6	NM_001254.4	MANE Select	c.438T>C	p.Cys146Cys	synonymous	Exon 3 of 12	NP_001245.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC6	ENST00000209728.9	TSL:1 MANE Select	c.438T>C	p.Cys146Cys	synonymous	Exon 3 of 12	ENSP00000209728.4
	CDC6	ENST00000936767.1		c.438T>C	p.Cys146Cys	synonymous	Exon 3 of 13	ENSP00000606826.1
	CDC6	ENST00000936770.1		c.438T>C	p.Cys146Cys	synonymous	Exon 3 of 12	ENSP00000606829.1

Frequencies

GnomAD3 genomes AF: 0.0969 AC: 14749 AN: 152140 Hom.: 2441 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0732

GnomAD2 exomes AF: 0.0251 AC: 6307 AN: 251192 AF XY: 0.0184

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00992 AC: 14503 AN: 1461858 Hom.: 2121 Cov.: 33 AF XY: 0.00852 AC XY: 6199 AN XY: 727226

African (AFR) AF: 0.344 AC: 11518 AN: 33470

American (AMR) AF: 0.0188 AC: 843 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000986 AC: 85 AN: 86248

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5768

European-Non Finnish (NFE) AF: 0.000486 AC: 540 AN: 1111998

Other (OTH) AF: 0.0230 AC: 1392 AN: 60396

GnomAD4 genome AF: 0.0972 AC: 14800 AN: 152258 Hom.: 2456 Cov.: 32 AF XY: 0.0946 AC XY: 7040 AN XY: 74450

African (AFR) AF: 0.339 AC: 14060 AN: 41498

American (AMR) AF: 0.0324 AC: 496 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68032

Other (OTH) AF: 0.0724 AC: 153 AN: 2112

Alfa AF: 0.0399 Hom.: 1485

Bravo AF: 0.110

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Meier-Gorlin syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.90
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1130199; hg19: chr17-38447569;