rs75175362

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.1141G>A(p.Asp381Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 1,584,976 control chromosomes in the GnomAD database, including 3,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D381H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.053 ( 278 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2844 hom. )

Consequence

CCDC8
NM_032040.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.104

Publications

22 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=8.3327293E-4).

BP6

Variant 19-46411670-C-T is Benign according to our data. Variant chr19-46411670-C-T is described in ClinVar as Benign. ClinVar VariationId is 262003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC8	NM_032040.5 link	c.1141G>A	p.Asp381Asn	missense_variant	Exon 1 of 1	ENST00000307522.5	NP_114429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC8	ENST00000307522.5 link	c.1141G>A	p.Asp381Asn	missense_variant	Exon 1 of 1	6	NM_032040.5	ENSP00000303158.3
CCDC8	ENST00000697726.1 link	c.1351G>A	p.Asp451Asn	missense_variant	Exon 1 of 1			ENSP00000513420.1

Frequencies

GnomAD3 genomes

AF:

0.0528

AC:

8030

AN:

152012

Hom.:

281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0292

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0493

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.0804

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0489

Gnomad OTH

AF:

0.0489

GnomAD2 exomes

AF:

0.0715

AC:

17985

AN:

251490

AF XY:

0.0701

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.0956

Gnomad ASJ exome

AF:

0.0323

Gnomad EAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.0995

Gnomad NFE exome

AF:

0.0495

Gnomad OTH exome

AF:

0.0591

GnomAD4 exome

AF:

0.0563

AC:

80732

AN:

1432846

Hom.:

2844

Cov.:

AF XY:

0.0568

AC XY:

40365

AN XY:

710944

show subpopulations

African (AFR)

AF:

0.0285

AC:

932

AN:

32752

American (AMR)

AF:

0.0919

AC:

3968

AN:

43170

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

817

AN:

25188

East Asian (EAS)

AF:

0.158

AC:

6073

AN:

38410

South Asian (SAS)

AF:

0.0768

AC:

6176

AN:

80386

European-Finnish (FIN)

AF:

0.102

AC:

5367

AN:

52804

Middle Eastern (MID)

AF:

0.0200

AC:

113

AN:

5662

European-Non Finnish (NFE)

AF:

0.0491

AC:

53835

AN:

1095344

Other (OTH)

AF:

0.0584

AC:

3451

AN:

59130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

6528

13055

19583

26110

32638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2124

4248

6372

8496

10620

<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:

0.0528

AC:

8030

AN:

152130

Hom.:

278

Cov.:

AF XY:

0.0554

AC XY:

4119

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0291

AC:

1208

AN:

41518

American (AMR)

AF:

0.0494

AC:

755

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3470

East Asian (EAS)

AF:

0.178

AC:

916

AN:

5140

South Asian (SAS)

AF:

0.0800

AC:

386

AN:

4822

European-Finnish (FIN)

AF:

0.107

AC:

1134

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0489

AC:

3321

AN:

67972

Other (OTH)

AF:

0.0503

AC:

106

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

360

720

1081

1441

1801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0499

Hom.:

691

Bravo

AF:

0.0499

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.0304

AC:

134

ESP6500EA

AF:

0.0466

AC:

401

ExAC

AF:

0.0695

AC:

8439

Asia WGS

AF:

0.131

AC:

455

AN:

3478

EpiCase

AF:

0.0443

EpiControl

AF:

0.0440

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0024

T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.35

.;T

MetaRNN

Benign

0.00083

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.90

L;L

PhyloP100

-0.10

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.68

.;N

REVEL

Benign

0.043

Sift

Benign

0.15

.;T

Sift4G

Benign

0.40

.;T

Polyphen

0.36

B;B

Vest4

0.015

MPC

0.41

ClinPred

0.0016

GERP RS

1.8

Varity_R

0.027

gMVP

0.076

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over