rs201502401

chr4-15599699-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001378615.1(CC2D2A):c.4667A>T(p.Asp1556Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,602,888 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1556H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant 4-15599699-A-T is Pathogenic according to our data. Variant chr4-15599699-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15599699-A-T is described in Lovd as [Pathogenic]. Variant chr4-15599699-A-T is described in Lovd as [Pathogenic]. Variant chr4-15599699-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.4667A>T	p.Asp1556Val	missense_variant	36/37	ENST00000424120.6
CC2D2A	NM_001080522.2	c.4667A>T	p.Asp1556Val	missense_variant	37/38
CC2D2A	NM_001378617.1	c.4520A>T	p.Asp1507Val	missense_variant	34/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.4667A>T	p.Asp1556Val	missense_variant	36/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 50 AN: 246244 Hom.: 0 AF XY: 0.000217 AC XY: 29 AN XY: 133502

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000313 AC: 454 AN: 1450570 Hom.: 0 Cov.: 30 AF XY: 0.000354 AC XY: 255 AN XY: 719874

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.000181

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: 0.000391

Gnomad4 OTH exome AF: 0.000184

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000166 AC: 20

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 33084218, 22425360, 22241855, 23012439, 19777577, 26477546, 26092869, 30609409, 31618753, 33486889, 34426522, 32488064) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2021	- -

Joubert syndrome 9 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. NMD-predicted variants resulting in loss of protein function have previously been reported in this gene (ClinVar). (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an aspartate to a valine (exon 37). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (51 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple individuals with Joubert syndrome (ClinVar; PMID 26477546; PMID 22241855). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1556 of the CC2D2A protein (p.Asp1556Val). This variant is present in population databases (rs201502401, gnomAD 0.04%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 19777577, 22241855, 22425360, 23012439, 26092869, 26477546). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217607). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

CC2D2A-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 23, 2023

The CC2D2A c.4667A>T variant is predicted to result in the amino acid substitution p.Asp1556Val. This variant has been reported in multiple individuals with Joubert syndrome (for examples see Mougou-Zerelli et al. 2009. PubMedID: 19777577; Srour et al. 2012. PubMedID: 22425360; Bachmann-Gagescu et al. 2015. PubMedID: 26092869; Srour et al. 2015. PubMed ID: 26477546). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2017

- -

COACH syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Feb 08, 2022

- -

Joubert syndrome and related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 14, 2023

Variant summary: CC2D2A c.4667A>T (p.Asp1556Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 246244 control chromosomes. c.4667A>T has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (Examples: Bachmann-Gagescu_2015, Schueler_2016, Srour_2012, Srour_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 26673778, 22425360, 26477546). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic (n=10), likely pathogenic (n=2) and VUS (n=1), citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 15, 2019

The p.Asp1556Val variant in CC2D2A has been reported in the compound heterozygous state in at least 7 individuals with Joubert syndrome (Mougou-Zerelli 2009, Bachmann-Gagescu 2015, Srour 2015, Fleming 2017). It segregated with disease in 1 affected family member (Srour 2015). This variant was also detected in 0.035% (45/127440) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Additionally, this variant has been classified as Pathogenic in ClinVar (Variation ID 217607). In summary, the p.Asp1556Val variant meets criteria to be classified as pathogenic for Joubert syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP1. -

CC2D2A-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2018

The CC2D2A c.4667A>T (p.Asp1556Val) missense variant has been reported in six studies in which it is found in 20 individuals with Joubert syndrome, including in 19 in a compound heterozygous state (including two sibling pairs) and in one individual in a heterozygous state in whom a second variant was not found (Mougou-Zerelli et. al. 2009; Bachmann-Gagescu et. al. 2012; Srour et. al. 2012a; Srour et. al. 2012b; Srour et. al. 2015; Bachmann-Gagescu et. al. 2015). The variant was also found in a heterozygous state in one unaffected individual. The variant has not been reported in individuals with Meckel syndrome. The p.Asp1556Val variant was absent from 2376 control chromosomes and is reported at a frequency of 0.00027 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Asp1556 residue is highly conserved. Based on the evidence, the p.Asp1556Val variant is classified as pathogenic for CC2D2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	-0.0034	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.89
MVP		0.93
MPC		0.11
ClinPred		0.14	T
GERP RS		5.8
Varity_R		0.47
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs201502401; hg19: chr4-15601322;