rs143086771

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032040.5(CCDC8):c.954T>G(p.Asn318Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,613,626 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 41 hom. )

Consequence

CCDC8
NM_032040.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.02

Publications

6 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=0.0042613447).

BP6

Variant 19-46411857-A-C is Benign according to our data. Variant chr19-46411857-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00441 (671/152036) while in subpopulation AMR AF = 0.00903 (138/15290). AF 95% confidence interval is 0.0078. There are 2 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC8	NM_032040.5 link	c.954T>G	p.Asn318Lys	missense_variant	Exon 1 of 1	ENST00000307522.5	NP_114429.2	Q9H0W5G8IFA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC8	ENST00000307522.5 link	c.954T>G	p.Asn318Lys	missense_variant	Exon 1 of 1	6	NM_032040.5	ENSP00000303158.3		Q9H0W5
CCDC8	ENST00000697726.1 link	c.1164T>G	p.Asn388Lys	missense_variant	Exon 1 of 1			ENSP00000513420.1		A0A8V8TMN3

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

673

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00904

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.000662

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00597

Gnomad OTH

AF:

0.00815

GnomAD2 exomes

AF:

0.00543

AC:

1366

AN:

251366

AF XY:

0.00570

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00711

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00695

Gnomad OTH exome

AF:

0.00995

GnomAD4 exome

AF:

0.00626

AC:

9155

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

4593

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33480

American (AMR)

AF:

0.00691

AC:

309

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

285

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00434

AC:

374

AN:

86240

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00679

AC:

7554

AN:

1111762

Other (OTH)

AF:

0.00787

AC:

475

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

705

1410

2114

2819

3524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.00441

AC:

671

AN:

152036

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

336

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41460

American (AMR)

AF:

0.00903

AC:

138

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00519

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000662

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00597

AC:

406

AN:

67950

Other (OTH)

AF:

0.00806

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00621

Hom.:

Bravo

AF:

0.00533

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00502

AC:

610

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00791

EpiControl

AF:

0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CCDC8: BP4, BS2 -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.30

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.5

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.41

.;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L

PhyloP100

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.55

.;N

REVEL

Benign

0.013

Sift

Uncertain

0.0050

.;D

Sift4G

Benign

0.80

.;T

Polyphen

0.36

B;B

Vest4

0.069

MutPred

0.33

Gain of ubiquitination at N318 (P = 0.0075);Gain of ubiquitination at N318 (P = 0.0075);

MVP

0.23

MPC

0.39

ClinPred

0.0060

GERP RS

-5.7

Varity_R

0.076

gMVP

0.094

Mutation Taster

=100/0

polymorphism

(source)

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

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