rs376969878

Variant names:

• chr4-15515957-C-T
• rs376969878
• NM_001378615.1:c.970C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-15515957-C-T
• chr4-15515957-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378615.1(CC2D2A):​c.970C>T​(p.Arg324Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000506 in 1,580,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R324H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.472
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10239595).

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.970C>T	p.Arg324Cys	missense	Exon 10 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.970C>T	p.Arg324Cys	missense	Exon 11 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.823C>T	p.Arg275Cys	missense	Exon 8 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.970C>T	p.Arg324Cys	missense	Exon 10 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.970C>T	p.Arg324Cys	missense	Exon 11 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.1150C>T		non_coding_transcript_exon	Exon 10 of 18

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000896 AC: 18 AN: 200962 AF XY: 0.0000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.0000695

Gnomad FIN exome AF: 0.0000531

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000518 AC: 74 AN: 1428364 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 35 AN XY: 707090

African (AFR) AF: 0.0000611 AC: 2 AN: 32754

American (AMR) AF: 0.000100 AC: 4 AN: 40000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37940

South Asian (SAS) AF: 0.0000617 AC: 5 AN: 81016

European-Finnish (FIN) AF: 0.0000584 AC: 3 AN: 51406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000484 AC: 53 AN: 1094876

Other (OTH) AF: 0.0000845 AC: 5 AN: 59162

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74264

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000415 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Joubert syndrome 9 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	1	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.47
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.067
Sift	Uncertain	0.019	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.17
MVP		0.41
MPC		0.054
ClinPred		0.24	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.47
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs376969878; hg19: chr4-15517580;