rs201502401

Variant names:

• chr4-15599699-A-T
• rs201502401
• NM_001378615.1:c.4667A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 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:20
• Conservation: PhyloP100: 8.95
• Publications: 6 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001378615.1
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 217607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.4667A>T	p.Asp1556Val	missense	Exon 36 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.4667A>T	p.Asp1556Val	missense	Exon 37 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.4520A>T	p.Asp1507Val	missense	Exon 34 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4667A>T	p.Asp1556Val	missense	Exon 36 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.4667A>T	p.Asp1556Val	missense	Exon 37 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.*225A>T		non_coding_transcript_exon	Exon 33 of 34	ENSP00000488669.2	A0A0J9YY35

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

GnomAD2 exomes AF: 0.000203 AC: 50 AN: 246244 AF XY: 0.000217

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 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

African (AFR) AF: 0.0000901 AC: 3 AN: 33290

American (AMR) AF: 0.000181 AC: 8 AN: 44086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000391 AC: 432 AN: 1103732

Other (OTH) AF: 0.000184 AC: 11 AN: 59908

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

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

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

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Joubert syndrome 9 (3)
2	-	-	CC2D2A-related disorder (2)
1	-	-	Ciliopathy (1)
1	-	-	COACH syndrome 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 (1)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.0034	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201502401; hg19: chr4-15601322;