Genetic Variant NM_001378615.1:c.1676T>G (chr4-15536988-T-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PM5PP5_ModerateBP4

The NM_001378615.1(CC2D2A):c.1676T>G(p.Leu559Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L559P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.67

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-15536988-T-C is described in Lovd as [Pathogenic].

PP5

Variant 4-15536988-T-G is Pathogenic according to our data. Variant chr4-15536988-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1499411.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.35300577). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.1676T>G	p.Leu559Arg	missense_variant	Exon 15 of 37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.1676T>G	p.Leu559Arg	missense_variant	Exon 15 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461522

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Pathogenic:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1499411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function. This variant disrupts the p.Leu559 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21068128, 26092869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 559 of the CC2D2A protein (p.Leu559Arg). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.018

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.16

Sift

Benign

0.036

D;D;D

Sift4G

Uncertain

0.0040

D;T;D

Polyphen

1.0

D;.;D

Vest4

0.60

MutPred

0.39

Gain of glycosylation at T564 (P = 0.0325);Gain of glycosylation at T564 (P = 0.0325);Gain of glycosylation at T564 (P = 0.0325);

MVP

0.49

MPC

0.082

ClinPred

0.88

GERP RS

5.6

Varity_R

0.48

gMVP

0.70

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over