dbSNP rs267606709: CC2D2A:p.Thr1116Met (chr4-15567735-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_001378615.1(CC2D2A):c.3347C>T(p.Thr1116Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,604,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1116T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.63

Publications

8 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
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:

LOC124900671 (HGNC:):

LOC124900671 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001378615.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

PP5

Variant 4-15567735-C-T is Pathogenic according to our data. Variant chr4-15567735-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 748.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CC2D2A	NM_001378615.1	MANE Select	c.3347C>T	p.Thr1116Met	missense	Exon 26 of 37	NP_001365544.1	Q9P2K1-4
CC2D2A	NM_001080522.2		c.3347C>T	p.Thr1116Met	missense	Exon 27 of 38	NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1		c.3200C>T	p.Thr1067Met	missense	Exon 24 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.3347C>T	p.Thr1116Met	missense	Exon 26 of 37	ENSP00000403465.1	Q9P2K1-4
CC2D2A	ENST00000503292.6	TSL:1	c.3347C>T	p.Thr1116Met	missense	Exon 27 of 38	ENSP00000421809.1	Q9P2K1-4
CC2D2A	ENST00000634028.2	TSL:1	n.3200C>T		non_coding_transcript_exon	Exon 23 of 34	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000377

AC:

AN:

238476

AF XY:

0.0000309

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000545

Gnomad OTH exome

AF:

0.000516

GnomAD4 exome

AF:

0.0000626

AC:

AN:

1452558

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

722328

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32860

American (AMR)

AF:

0.00

AC:

AN:

41952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000784

AC:

AN:

1109550

Other (OTH)

AF:

0.0000333

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000745

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

COACH syndrome 2 (1)

Joubert syndrome 9 (1)

Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.0

PhyloP100

7.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.59

Sift

Uncertain

0.012

Sift4G

Uncertain

0.053

Polyphen

1.0

Vest4

0.69

MVP

0.94

MPC

0.13

ClinPred

0.61

GERP RS

5.2

Varity_R

0.16

gMVP

0.75

Mutation Taster

=2/98

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over