chr4-15574128-C-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.3595-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,514,516 control chromosomes in the GnomAD database, including 62,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5625 hom., cov: 32)

Exomes 𝑓: 0.29 ( 56640 hom. )

Consequence

CC2D2A
NM_001378615.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.509

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=-0.55).

BP6

Variant 4-15574128-C-T is Benign according to our data. Variant chr4-15574128-C-T is described in ClinVar as Benign. ClinVar VariationId is 126241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.3595-22C>T	intron_variant	Intron 28 of 36	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 link	c.3595-22C>T	intron_variant	Intron 29 of 37		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 link	c.3448-22C>T	intron_variant	Intron 26 of 34		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.3595-22C>T		intron_variant	Intron 28 of 36	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

40567

AN:

151996

Hom.:

5609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.265

Gnomad EAS

AF:

0.459

Gnomad SAS

AF:

0.293

Gnomad FIN

AF:

0.321

Gnomad MID

AF:

0.287

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.283

GnomAD2 exomes

AF:

0.284

AC:

39296

AN:

138486

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.476

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.283

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.285

AC:

388598

AN:

1362402

Hom.:

56640

Cov.:

AF XY:

0.285

AC XY:

190631

AN XY:

669424

show subpopulations

African (AFR)

AF:

0.226

AC:

6879

AN:

30388

American (AMR)

AF:

0.205

AC:

6619

AN:

32364

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

6671

AN:

23948

East Asian (EAS)

AF:

0.434

AC:

15236

AN:

35088

South Asian (SAS)

AF:

0.285

AC:

21386

AN:

75090

European-Finnish (FIN)

AF:

0.318

AC:

15434

AN:

48562

Middle Eastern (MID)

AF:

0.276

AC:

1234

AN:

4474

European-Non Finnish (NFE)

AF:

0.283

AC:

298674

AN:

1056164

Other (OTH)

AF:

0.292

AC:

16465

AN:

56324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

12598

25195

37793

50390

62988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10276

20552

30828

41104

51380

<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:

0.267

AC:

40602

AN:

152114

Hom.:

5625

Cov.:

AF XY:

0.271

AC XY:

20120

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.224

AC:

9286

AN:

41520

American (AMR)

AF:

0.224

AC:

3424

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

918

AN:

3470

East Asian (EAS)

AF:

0.459

AC:

2373

AN:

5166

South Asian (SAS)

AF:

0.294

AC:

1416

AN:

4820

European-Finnish (FIN)

AF:

0.321

AC:

3398

AN:

10574

Middle Eastern (MID)

AF:

0.301

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.279

AC:

18970

AN:

67974

Other (OTH)

AF:

0.289

AC:

608

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1553

3106

4659

6212

7765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.274

Hom.:

1102

Bravo

AF:

0.257

Asia WGS

AF:

0.344

AC:

1197

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

-0.55

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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