4-15586274-A-T

Variant names:

Variant summary

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

The NM_001378615.1(CC2D2A):c.4065+28A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,395,038 control chromosomes in the GnomAD database, including 686,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70174 hom., cov: 31)

Exomes 𝑓: 1.0 ( 616635 hom. )

Consequence

CC2D2A
NM_001378615.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.206

Publications

9 publications found

Variant links:

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
retinitis pigmentosa 93
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
COACH syndrome 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CC2D2A 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 (BayesDel_noAF=-0.92).

BP6

Variant 4-15586274-A-T is Benign according to our data. Variant chr4-15586274-A-T is described in ClinVar as Benign. ClinVar VariationId is 126243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CC2D2A	NM_001378615.1 link	c.4065+28A>T	intron_variant	Intron 31 of 36	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.4065+28A>T	intron_variant	Intron 32 of 37		NP_001073991.2
CC2D2A	NM_001378617.1 link	c.3918+28A>T	intron_variant	Intron 29 of 34		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.4065+28A>T		intron_variant	Intron 31 of 36	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes

AF:

0.958

AC:

145776

AN:

152178

Hom.:

70128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.854

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.983

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.987

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.969

GnomAD2 exomes

AF:

0.990

AC:

205033

AN:

207164

AF XY:

0.992

show subpopulations

Gnomad AFR exome

AF:

0.855

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.996

GnomAD4 exome

AF:

0.996

AC:

1237702

AN:

1242742

Hom.:

616635

Cov.:

AF XY:

0.996

AC XY:

616833

AN XY:

619042

show subpopulations

African (AFR)

AF:

0.858

AC:

24023

AN:

27988

American (AMR)

AF:

0.991

AC:

33303

AN:

33596

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

22542

AN:

22542

East Asian (EAS)

AF:

1.00

AC:

35753

AN:

35756

South Asian (SAS)

AF:

1.00

AC:

63081

AN:

63096

European-Finnish (FIN)

AF:

1.00

AC:

50230

AN:

50230

Middle Eastern (MID)

AF:

0.994

AC:

5149

AN:

5182

European-Non Finnish (NFE)

AF:

1.00

AC:

952297

AN:

952506

Other (OTH)

AF:

0.990

AC:

51324

AN:

51846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

221

443

664

886

1107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18684

37368

56052

74736

93420

<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:

0.958

AC:

145881

AN:

152296

Hom.:

70174

Cov.:

AF XY:

0.960

AC XY:

71458

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.854

AC:

35481

AN:

41526

American (AMR)

AF:

0.983

AC:

15045

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5183

AN:

5184

South Asian (SAS)

AF:

0.999

AC:

4823

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10622

AN:

10622

Middle Eastern (MID)

AF:

0.986

AC:

290

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

68006

AN:

68046

Other (OTH)

AF:

0.969

AC:

2049

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

282

563

845

1126

1408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.981

Hom.:

13489

Bravo

AF:

0.953

Asia WGS

AF:

0.988

AC:

3437

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Meckel syndrome, type 6

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome 9

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.62

(source)

DANN

Benign

0.73

PhyloP100

0.21

Mutation Taster

=100/0

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