rs372671421

Variant names:

• chr4-15589661-T-C
• rs372671421
• NM_001378615.1:c.4296T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001080522.2(CC2D2A):​c.4296T>C​(p.Cys1432Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000599 in 1,595,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: CC2D2A NM_001080522.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 0.442
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-15589661-T-C is Benign according to our data. Variant chr4-15589661-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210611.
• BP7: Synonymous conserved (PhyloP=0.442 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080522.2. 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.4296T>C	p.Cys1432Cys	synonymous	Exon 33 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.4296T>C	p.Cys1432Cys	synonymous	Exon 34 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.4149T>C	p.Cys1383Cys	synonymous	Exon 31 of 35	NP_001365546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.4296T>C	p.Cys1432Cys	synonymous	Exon 33 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.4296T>C	p.Cys1432Cys	synonymous	Exon 34 of 38	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.4149T>C		non_coding_transcript_exon	Exon 30 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000317 AC: 77 AN: 242586 AF XY: 0.000311

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000621

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000627 AC: 905 AN: 1443170 Hom.: 1 Cov.: 30 AF XY: 0.000601 AC XY: 431 AN XY: 717564

African (AFR) AF: 0.0000302 AC: 1 AN: 33064

American (AMR) AF: 0.0000231 AC: 1 AN: 43352

Ashkenazi Jewish (ASJ) AF: 0.000468 AC: 12 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 39104

South Asian (SAS) AF: 0.00 AC: 0 AN: 82506

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000793 AC: 873 AN: 1101426

Other (OTH) AF: 0.000286 AC: 17 AN: 59500

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74324

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000355

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	1	not specified (2)
-	1	-	CC2D2A-related disorder (1)
-	1	-	Joubert syndrome 9 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.7
DANN	Benign	0.59
PhyloP100		0.44
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs372671421; hg19: chr4-15591284;