4-15596207-G-T

Variant names:

• chr4-15596207-G-T
• rs878854168
• NM_001378615.1:c.4437G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378615.1(CC2D2A):​c.4437G>T​(p.Gln1479His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000368 in 1,357,610 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1479Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 0 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.4437G>T	p.Gln1479His	missense splice_region	Exon 34 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.4437G>T	p.Gln1479His	missense splice_region	Exon 35 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.4290G>T	p.Gln1430His	missense splice_region	Exon 32 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.4437G>T	p.Gln1479His	missense splice_region	Exon 34 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.4437G>T	p.Gln1479His	missense splice_region	Exon 35 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.4231G>T		splice_region non_coding_transcript_exon	Exon 31 of 34	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1357610 Hom.: 0 Cov.: 29 AF XY: 0.00000299 AC XY: 2 AN XY: 668052

African (AFR) AF: 0.00 AC: 0 AN: 29398

American (AMR) AF: 0.00 AC: 0 AN: 27822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23532

East Asian (EAS) AF: 0.00 AC: 0 AN: 35236

South Asian (SAS) AF: 0.00 AC: 0 AN: 71090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4754

European-Non Finnish (NFE) AF: 0.00000471 AC: 5 AN: 1061638

Other (OTH) AF: 0.00 AC: 0 AN: 56092

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Benign	0.95
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.0039	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.30		Gain of glycosylation at S1476 (P = 0.0364)
MVP		0.93
MPC		0.12
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.86
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

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

Other links and lift over

dbSNP: rs878854168; hg19: chr4-15597830;