rs386833764

Variant names:

• chr4-15511381-GGAA-G
• rs386833764
• NM_001378615.1:c.685_687delGAA

Your query was ambiguous. Multiple possible variants found:

• chr4-15511381-GGAA-G
• chr4-15511381-GGAA-GGAAGAA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001378615.1(CC2D2A):​c.685_687delGAA​(p.Glu229del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,553,760 control chromosomes in the GnomAD database, including 4,624 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (314 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4310 hom.)
• Consequence: CC2D2A NM_001378615.1 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: 7.67
• Publications: 10 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

LOC124900672 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378615.1
• BP6: Variant 4-15511381-GGAA-G is Benign according to our data. Variant chr4-15511381-GGAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 56316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

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.685_687delGAA	p.Glu229del	conservative_inframe_deletion	Exon 8 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.685_687delGAA	p.Glu229del	conservative_inframe_deletion	Exon 9 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.538_540delGAA	p.Glu180del	conservative_inframe_deletion	Exon 6 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.685_687delGAA	p.Glu229del	conservative_inframe_deletion	Exon 8 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.685_687delGAA	p.Glu229del	conservative_inframe_deletion	Exon 9 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.865_867delGAA		non_coding_transcript_exon	Exon 8 of 18

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8512 AN: 152072 Hom.: 311 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0716

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0871

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0789

Gnomad OTH AF: 0.0541

GnomAD2 exomes AF: 0.0632 AC: 12273 AN: 194092 AF XY: 0.0649

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0443

Gnomad EAS exome AF: 0.0000808

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.0705

Gnomad OTH exome AF: 0.0580

GnomAD4 exome AF: 0.0752 AC: 105448 AN: 1401570 Hom.: 4310 AF XY: 0.0758 AC XY: 52702 AN XY: 695514

African (AFR) AF: 0.0107 AC: 313 AN: 29132

American (AMR) AF: 0.0839 AC: 2596 AN: 30930

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1146 AN: 24434

East Asian (EAS) AF: 0.000335 AC: 12 AN: 35808

South Asian (SAS) AF: 0.0908 AC: 6800 AN: 74904

European-Finnish (FIN) AF: 0.0641 AC: 3387 AN: 52878

Middle Eastern (MID) AF: 0.0523 AC: 294 AN: 5624

European-Non Finnish (NFE) AF: 0.0801 AC: 87355 AN: 1089894

Other (OTH) AF: 0.0612 AC: 3545 AN: 57966

GnomAD4 genome AF: 0.0560 AC: 8521 AN: 152190 Hom.: 314 Cov.: 32 AF XY: 0.0556 AC XY: 4136 AN XY: 74418

African (AFR) AF: 0.0153 AC: 634 AN: 41536

American (AMR) AF: 0.0720 AC: 1101 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.0872 AC: 420 AN: 4818

European-Finnish (FIN) AF: 0.0637 AC: 674 AN: 10588

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0789 AC: 5367 AN: 67998

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0186 Hom.: 64

Bravo AF: 0.0534

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	COACH syndrome 1 (1)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 1 (1)
1	-	-	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=61/39	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs386833764; hg19: chr4-15513004; COSMIC: COSV67504988;