rs201219078

Variant names:

• chr4-15601414-C-A
• rs201219078
• NM_001378615.1:c.4852C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-15601414-C-A
• chr4-15601414-C-G
• chr4-15601414-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378615.1(CC2D2A):​c.4852C>A​(p.Arg1618Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000752 in 1,330,304 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1618C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38
• Publications: 4 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.4852C>A	p.Arg1618Ser	missense	Exon 37 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.4852C>A	p.Arg1618Ser	missense	Exon 38 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.4705C>A	p.Arg1569Ser	missense	Exon 35 of 35	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4852C>A	p.Arg1618Ser	missense	Exon 37 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.4852C>A	p.Arg1618Ser	missense	Exon 38 of 38	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.*410C>A		non_coding_transcript_exon	Exon 34 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1330304 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 650748

African (AFR) AF: 0.00 AC: 0 AN: 29872

American (AMR) AF: 0.00 AC: 0 AN: 26250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21680

East Asian (EAS) AF: 0.00 AC: 0 AN: 37186

South Asian (SAS) AF: 0.00 AC: 0 AN: 63204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4904

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043688

Other (OTH) AF: 0.00 AC: 0 AN: 54740

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome Uncertain:1

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 955483). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1618 of the CC2D2A protein (p.Arg1618Ser).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.52		Loss of MoRF binding (P = 0.0076)
MVP		0.97
MPC		0.31
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.48
gMVP		0.80
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs201219078; hg19: chr4-15603037;