Genetic Variant CCDC66:p.Asp5Asn (chr3-56558847-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001141947.3(CCDC66):c.13G>A(p.Asp5Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCDC66
NM_001141947.3 missense, splice_region

Scores

Splicing: ADA: 0.2781

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141947.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC66	NM_001141947.3	MANE Select	c.13G>A	p.Asp5Asn	missense splice_region	Exon 2 of 18	NP_001135419.1	A2RUB6-1
CCDC66	NM_001353147.1		c.13G>A	p.Asp5Asn	missense splice_region	Exon 2 of 18	NP_001340076.1
CCDC66	NM_001353148.1		c.13G>A	p.Asp5Asn	missense splice_region	Exon 2 of 18	NP_001340077.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC66	ENST00000394672.8	TSL:1 MANE Select	c.13G>A	p.Asp5Asn	missense splice_region	Exon 2 of 18	ENSP00000378167.3	A2RUB6-1
CCDC66	ENST00000326595.11	TSL:1	c.-90G>A		splice_region	Exon 2 of 18	ENSP00000326050.7	A2RUB6-3
CCDC66	ENST00000326595.11	TSL:1	c.-90G>A		5_prime_UTR	Exon 2 of 18	ENSP00000326050.7	A2RUB6-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1394164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687926

African (AFR)

AF:

0.00

AC:

AN:

31484

American (AMR)

AF:

0.00

AC:

AN:

35650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25118

East Asian (EAS)

AF:

0.00

AC:

AN:

35540

South Asian (SAS)

AF:

0.00

AC:

AN:

78994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074844

Other (OTH)

AF:

0.00

AC:

AN:

57814

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.54

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PhyloP100

4.8

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.74

Vest4

0.65

MutPred

0.16

Loss of helix (P = 0.1299)

MVP

0.85

MPC

0.12

ClinPred

0.99

GERP RS

4.8

Varity_R

0.35

gMVP

0.78

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.28

dbscSNV1_RF

Benign

0.46

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over