rs886038409

Variant names:

• chr4-15570504-T-C
• rs886038409
• NM_001378615.1:c.3594+8T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378615.1(CC2D2A):​c.3594+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,419,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 splice_region, intron
• Scores: Splicing: ADA: 0.00006909
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00800
• Publications: 0 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

LOC124900671 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-15570504-T-C is Benign according to our data. Variant chr4-15570504-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 257389.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3594+8T>C		splice_region intron	N/A	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.3594+8T>C		splice_region intron	N/A	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.3447+8T>C		splice_region intron	N/A	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.3594+8T>C		splice_region intron	N/A	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.3594+8T>C		splice_region intron	N/A	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.3447+8T>C		splice_region intron	N/A	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1419926 Hom.: 0 Cov.: 23 AF XY: 0.00000849 AC XY: 6 AN XY: 706358

African (AFR) AF: 0.00 AC: 0 AN: 32764

American (AMR) AF: 0.00 AC: 0 AN: 42448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.00 AC: 0 AN: 39198

South Asian (SAS) AF: 0.00 AC: 0 AN: 82786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1079880

Other (OTH) AF: 0.00 AC: 0 AN: 58980

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.48
PhyloP100		0.0080

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0
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: rs886038409; hg19: chr4-15572127;