4-15516648-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_001378615.1(CC2D2A):​c.1041C>T​(p.Asp347Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,612,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00067 ( 1 hom. )

Consequence

CC2D2A
NM_001378615.1 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: -0.369
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BP6
Variant 4-15516648-C-T is Benign according to our data. Variant chr4-15516648-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=5}. Variant chr4-15516648-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.369 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CC2D2ANM_001378615.1 linkc.1041C>T p.Asp347Asp synonymous_variant Exon 11 of 37 ENST00000424120.6 NP_001365544.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CC2D2AENST00000424120.6 linkc.1041C>T p.Asp347Asp synonymous_variant Exon 11 of 37 5 NM_001378615.1 ENSP00000403465.1 Q9P2K1-4

Frequencies

GnomAD3 genomes
AF:
0.000644
AC:
98
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.000963
Gnomad SAS
AF:
0.00373
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000632
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000894
AC:
222
AN:
248248
Hom.:
0
AF XY:
0.00114
AC XY:
153
AN XY:
134690
show subpopulations
Gnomad AFR exome
AF:
0.0000650
Gnomad AMR exome
AF:
0.000350
Gnomad ASJ exome
AF:
0.00150
Gnomad EAS exome
AF:
0.000335
Gnomad SAS exome
AF:
0.00306
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.000808
Gnomad OTH exome
AF:
0.000496
GnomAD4 exome
AF:
0.000670
AC:
978
AN:
1460404
Hom.:
1
Cov.:
30
AF XY:
0.000776
AC XY:
564
AN XY:
726452
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000314
Gnomad4 ASJ exome
AF:
0.00104
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00294
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000560
Gnomad4 OTH exome
AF:
0.000879
GnomAD4 genome
AF:
0.000644
AC:
98
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.000699
AC XY:
52
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.000966
Gnomad4 SAS
AF:
0.00373
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000632
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000899
Hom.:
0
Bravo
AF:
0.000616
EpiCase
AF:
0.000820
EpiControl
AF:
0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Jul 16, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 07, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CC2D2A: BP4, BP7 -

Joubert syndrome 9 Uncertain:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4. -

Retinal dystrophy Uncertain:1
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Meckel syndrome, type 6 Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CC2D2A-related disorder Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.34
CADD
Benign
2.7
DANN
Benign
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371086728; hg19: chr4-15518271; COSMIC: COSV67503482; COSMIC: COSV67503482; API