4-15596207-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 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 same amino acid change has been previously reported as Uncertain significancein 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

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 Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.4437G>T	p.Gln1479His	missense_variant, splice_region_variant	34/37	ENST00000424120.6
CC2D2A	NM_001080522.2	c.4437G>T	p.Gln1479His	missense_variant, splice_region_variant	35/38
CC2D2A	NM_001378617.1	c.4290G>T	p.Gln1430His	missense_variant, splice_region_variant	32/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.4437G>T	p.Gln1479His	missense_variant, splice_region_variant	34/37	5	NM_001378615.1	P1

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

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: 0.00000471

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Uncertain	-0.0039	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.30		Gain of glycosylation at S1476 (P = 0.0364);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854168; hg19: chr4-15597830;