Genetic Variant NM_001141947.3:c.1379G>A (chr3-56594003-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001141947.3(CCDC66):c.1379G>A(p.Arg460Gln) variant causes a missense change. The variant allele was found at a frequency of 0.472 in 1,612,838 control chromosomes in the GnomAD database, including 194,875 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 0.38 ( 13692 hom., cov: 32)

Exomes 𝑓: 0.48 ( 181183 hom. )

Consequence

CCDC66
NM_001141947.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

Publications

57 publications found

Variant links:

Genes affected

CCDC66 (HGNC:27709): (coiled-coil domain containing 66) Enables microtubule binding activity. Involved in cilium assembly; microtubule bundle formation; and regulation of protein localization to cilium. Located in several cellular components, including Flemming body; microtubule cytoskeleton; and photoreceptor inner segment. [provided by Alliance of Genome Resources, Apr 2022]

CCDC66 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.8731775E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC66	NM_001141947.3 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 10 of 18	ENST00000394672.8	NP_001135419.1	A2RUB6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC66	ENST00000394672.8 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 10 of 18	1	NM_001141947.3	ENSP00000378167.3		A2RUB6-1

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

58105

AN:

151888

Hom.:

13695

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.0433

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.505

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.374

GnomAD2 exomes

AF:

0.393

AC:

98833

AN:

251334

AF XY:

0.401

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.224

Gnomad ASJ exome

AF:

0.561

Gnomad EAS exome

AF:

0.0360

Gnomad FIN exome

AF:

0.511

Gnomad NFE exome

AF:

0.537

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.482

AC:

703667

AN:

1460830

Hom.:

181183

Cov.:

AF XY:

0.478

AC XY:

347733

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.141

AC:

4732

AN:

33474

American (AMR)

AF:

0.237

AC:

10582

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

14659

AN:

26126

East Asian (EAS)

AF:

0.0681

AC:

2704

AN:

39688

South Asian (SAS)

AF:

0.252

AC:

21720

AN:

86226

European-Finnish (FIN)

AF:

0.516

AC:

27538

AN:

53410

Middle Eastern (MID)

AF:

0.482

AC:

2782

AN:

5766

European-Non Finnish (NFE)

AF:

0.533

AC:

592293

AN:

1111056

Other (OTH)

AF:

0.442

AC:

26657

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

17439

34878

52317

69756

87195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16192

32384

48576

64768

80960

<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:

0.382

AC:

58091

AN:

152008

Hom.:

13692

Cov.:

AF XY:

0.376

AC XY:

27922

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.153

AC:

6360

AN:

41452

American (AMR)

AF:

0.319

AC:

4878

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

2016

AN:

3470

East Asian (EAS)

AF:

0.0436

AC:

226

AN:

5184

South Asian (SAS)

AF:

0.231

AC:

1110

AN:

4814

European-Finnish (FIN)

AF:

0.505

AC:

5326

AN:

10550

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.542

AC:

36858

AN:

67948

Other (OTH)

AF:

0.370

AC:

781

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1591

3182

4773

6364

7955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<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:

0.478

Hom.:

89828

Bravo

AF:

0.357

TwinsUK

AF:

0.537

AC:

1991

ALSPAC

AF:

0.549

AC:

2115

ESP6500AA

AF:

0.154

AC:

678

ESP6500EA

AF:

0.537

AC:

4621

ExAC

AF:

0.396

AC:

48100

Asia WGS

AF:

0.144

AC:

504

AN:

3478

EpiCase

AF:

0.543

EpiControl

AF:

0.535

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.077

T;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.00079

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.3

.;M;.

PhyloP100

6.2

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.20

Sift

Benign

0.037

D;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.27, 0.38

MPC

0.12

ClinPred

0.019

GERP RS

5.8

Varity_R

0.26

gMVP

0.11

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Computational scores

Splicing

Publications

Other links and lift over