rs587779732

chr4-15596177-C-Achr4-15596177-C-Gchr4-15596177-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PS1_Moderate PM2 BP4_Moderate

The NM_001378615.1(CC2D2A):c.4407C>A(p.Ser1469Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,547,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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 Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1469S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

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 Uncertain_significance. Variant got 2 ACMG points.

• PS1: Transcript NM_001378615.1 (CC2D2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 126245
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22593799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.4407C>A	p.Ser1469Arg	missense_variant	34/37	ENST00000424120.6
CC2D2A	NM_001080522.2	c.4407C>A	p.Ser1469Arg	missense_variant	35/38
CC2D2A	NM_001378617.1	c.4260C>A	p.Ser1420Arg	missense_variant	32/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.4407C>A	p.Ser1469Arg	missense_variant	34/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000502 AC: 7 AN: 1395228 Hom.: 0 Cov.: 29 AF XY: 0.00000581 AC XY: 4 AN XY: 688140

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: 0.00000650

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	D;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.97	D;D;D;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.98	D;D
Vest4		0.24
MutPred		0.36		Gain of MoRF binding (P = 0.0331);Gain of MoRF binding (P = 0.0331);
MVP		0.64
MPC		0.049
ClinPred		0.97	D
GERP RS		-3.6
Varity_R		0.32
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587779732; hg19: chr4-15597800;