rs863225169

Positions:

• chr4-15567482-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001378615.1(CC2D2A):​c.3288G>C​(p.Gln1096His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000891 in 1,458,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.17

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]

LOC124900671 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 4-15567482-G-C is Pathogenic according to our data. Variant chr4-15567482-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217595.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}. Variant chr4-15567482-G-C is described in Lovd as [Pathogenic]. Variant chr4-15567482-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.3288G>C	p.Gln1096His	missense_variant, splice_region_variant	25/37	ENST00000424120.6	NP_001365544.1
LOC124900671	XR_007058061.1	n.130+3249C>G		intron_variant, non_coding_transcript_variant
CC2D2A	NM_001080522.2	c.3288G>C	p.Gln1096His	missense_variant, splice_region_variant	26/38		NP_001073991.2
CC2D2A	NM_001378617.1	c.3141G>C	p.Gln1047His	missense_variant, splice_region_variant	23/35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.3288G>C	p.Gln1096His	missense_variant, splice_region_variant	25/37	5	NM_001378615.1	ENSP00000403465	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458546 Hom.: 0 Cov.: 34 AF XY: 0.00000827 AC XY: 6 AN XY: 725604

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ciliopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 01, 2024

This sequence change in CC2D2A is predicted to replace glutamine with histidine at codon 1096, p.(Gln1096His). The glutamine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the C2 domain. There is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 25 of the CC2D2A coding sequence, which is part of the consensus splice site for this exon. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.001% (13/1,110,402 alleles) in the European (non-Finnish) population, consistent with a recessive disease. This variant has been detected in at least two individuals (compound heterozygous with a pathogenic variant on the other allele) with a phenotype consistent with a ciliopathy (Joubert syndrome; PMID: 18950740, 38259611). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change and predicts a deleterious effect for the missense substitution (REVEL = 0.808). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM3_Strong, PP3. -

Joubert syndrome 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in combination with another CC2D2A variant in an individual affected with Joubert syndrome (PMID: 18950740). ClinVar contains an entry for this variant (Variation ID: 217595). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 1096 of the CC2D2A protein (p.Gln1096His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 26 of the CC2D2A coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.92	P;P
Vest4		0.67
MutPred		0.68		Gain of glycosylation at Y1092 (P = 0.0067);Gain of glycosylation at Y1092 (P = 0.0067);
MVP		0.94
MPC		0.27
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225169; hg19: chr4-15569105;