NM_032040.5:c.1521G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032040.5(CCDC8):c.1521G>C(p.Lys507Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,614,146 control chromosomes in the GnomAD database, including 3,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 296 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2870 hom. )

Consequence

CCDC8
NM_032040.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.56

Publications

20 publications found

Variant links:

Genes affected

CCDC8 (HGNC:25367): (coiled-coil domain containing 8) This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a cofactor required for p53-mediated apoptosis following DNA damage, and may also play a role in growth through interactions with the cytoskeletal adaptor protein obscurin-like 1. Mutations in this gene are a cause of 3M syndrome-3 (3M3). [provided by RefSeq, Dec 2011]

CCDC8 Gene-Disease associations (from GenCC):

3M syndrome 3
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
3-M syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
spinocerebellar ataxia type 40
Inheritance: AD Classification: LIMITED Submitted by: Illumina

CCDC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014494061).

BP6

Variant 19-46411290-C-G is Benign according to our data. Variant chr19-46411290-C-G is described in ClinVar as Benign. ClinVar VariationId is 262004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032040.5. 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
	CCDC8	NM_032040.5	MANE Select	c.1521G>C	p.Lys507Asn	missense	Exon 1 of 1	NP_114429.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC8	ENST00000307522.5	TSL:6 MANE Select	c.1521G>C	p.Lys507Asn	missense	Exon 1 of 1	ENSP00000303158.3
	CCDC8	ENST00000697726.1		c.1731G>C	p.Lys577Asn	missense	Exon 1 of 1	ENSP00000513420.1

Frequencies

GnomAD3 genomes

AF:

0.0560

AC:

8522

AN:

152148

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.0521

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.0813

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0726

AC:

18247

AN:

251422

AF XY:

0.0710

show subpopulations

Gnomad AFR exome

AF:

0.0375

Gnomad AMR exome

AF:

0.0970

Gnomad ASJ exome

AF:

0.0327

Gnomad EAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.0995

Gnomad NFE exome

AF:

0.0498

Gnomad OTH exome

AF:

0.0590

GnomAD4 exome

AF:

0.0558

AC:

81559

AN:

1461880

Hom.:

2870

Cov.:

AF XY:

0.0561

AC XY:

40765

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0366

AC:

1227

AN:

33480

American (AMR)

AF:

0.0900

AC:

4026

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

828

AN:

26136

East Asian (EAS)

AF:

0.153

AC:

6078

AN:

39700

South Asian (SAS)

AF:

0.0717

AC:

6189

AN:

86258

European-Finnish (FIN)

AF:

0.101

AC:

5375

AN:

53410

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5768

European-Non Finnish (NFE)

AF:

0.0487

AC:

54209

AN:

1112008

Other (OTH)

AF:

0.0581

AC:

3511

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

5239

10478

15718

20957

26196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2138

4276

6414

8552

10690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0560

AC:

8526

AN:

152266

Hom.:

296

Cov.:

AF XY:

0.0587

AC XY:

4369

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0379

AC:

1574

AN:

41558

American (AMR)

AF:

0.0522

AC:

799

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3472

East Asian (EAS)

AF:

0.181

AC:

936

AN:

5174

South Asian (SAS)

AF:

0.0810

AC:

391

AN:

4830

European-Finnish (FIN)

AF:

0.108

AC:

1142

AN:

10608

Middle Eastern (MID)

AF:

0.0411

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0494

AC:

3360

AN:

68002

Other (OTH)

AF:

0.0545

AC:

115

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

418

835

1253

1670

2088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0519

Hom.:

225

Bravo

AF:

0.0534

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0496

AC:

191

ESP6500AA

AF:

0.0381

AC:

168

ESP6500EA

AF:

0.0474

AC:

408

ExAC

AF:

0.0707

AC:

8585

Asia WGS

AF:

0.132

AC:

459

AN:

3478

EpiCase

AF:

0.0454

EpiControl

AF:

0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0041

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

1.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

REVEL

Benign

0.10

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.050

Polyphen

0.90

Vest4

0.088

MutPred

0.076

Loss of methylation at K507 (P = 0.0061)

MPC

0.87

ClinPred

0.022

GERP RS

4.0

Varity_R

0.55

gMVP

0.15

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over