rs2077464

Variant names:

• chr17-40290312-A-G
• rs2077464
• NM_001254.4:c.178+714A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001254.4(CDC6):​c.178+714A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,014 control chromosomes in the GnomAD database, including 6,268 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (6268 hom., cov: 32)
• Consequence: CDC6 NM_001254.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC6	NM_001254.4	MANE Select	c.178+714A>G		intron	N/A	NP_001245.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC6	ENST00000209728.9	TSL:1 MANE Select	c.178+714A>G		intron	N/A	ENSP00000209728.4
	CDC6	ENST00000649662.1		c.178+714A>G		intron	N/A	ENSP00000497345.1
	CDC6	ENST00000580824.5	TSL:3	c.178+714A>G		intron	N/A	ENSP00000463635.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36326 AN: 151896 Hom.: 6228 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.240 AC: 36427 AN: 152014 Hom.: 6268 Cov.: 32 AF XY: 0.239 AC XY: 17725 AN XY: 74282

African (AFR) AF: 0.488 AC: 20194 AN: 41416

American (AMR) AF: 0.173 AC: 2640 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3470

East Asian (EAS) AF: 0.353 AC: 1828 AN: 5174

South Asian (SAS) AF: 0.109 AC: 528 AN: 4822

European-Finnish (FIN) AF: 0.143 AC: 1515 AN: 10566

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8753 AN: 67972

Other (OTH) AF: 0.194 AC: 410 AN: 2114

Alfa AF: 0.164 Hom.: 3514

Bravo AF: 0.255

Asia WGS AF: 0.239 AC: 832 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.3
DANN	Benign	0.76
PhyloP100		0.046
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: rs2077464; hg19: chr17-38446564;