chr4-15480698-C-T

Variant names:

• chr4-15480698-C-T
• rs1861049
• NM_001378615.1:c.124-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378615.1(CC2D2A):​c.124-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,606,312 control chromosomes in the GnomAD database, including 11,290 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4244 hom., cov: 31)
  • Exomes 𝑓: 0.061 (7046 hom.)
• Consequence: CC2D2A NM_001378615.1 splice_region, intron
• Scores: Splicing: ADA: 0.00002531
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.06
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-15480698-C-T is Benign according to our data. Variant chr4-15480698-C-T is described in ClinVar as Benign. ClinVar VariationId is 93531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 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.124-6C>T		splice_region intron	N/A	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.124-6C>T		splice_region intron	N/A	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.-24-6C>T		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.124-6C>T		splice_region intron	N/A	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.124-6C>T		splice_region intron	N/A	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000503658.2	TSL:1	c.230-6C>T		splice_region intron	N/A	ENSP00000426846.1	Q9P2K1-5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25398 AN: 151832 Hom.: 4238 Cov.: 31

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.110 AC: 26052 AN: 236020 AF XY: 0.0975

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.00858

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0367

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.0612 AC: 89070 AN: 1454362 Hom.: 7046 Cov.: 29 AF XY: 0.0600 AC XY: 43400 AN XY: 722902

African (AFR) AF: 0.436 AC: 14493 AN: 33260

American (AMR) AF: 0.269 AC: 11622 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.00933 AC: 242 AN: 25934

East Asian (EAS) AF: 0.164 AC: 6464 AN: 39340

South Asian (SAS) AF: 0.0976 AC: 8281 AN: 84806

European-Finnish (FIN) AF: 0.0553 AC: 2934 AN: 53024

Middle Eastern (MID) AF: 0.0578 AC: 332 AN: 5748

European-Non Finnish (NFE) AF: 0.0361 AC: 40062 AN: 1108908

Other (OTH) AF: 0.0771 AC: 4640 AN: 60146

GnomAD4 genome AF: 0.167 AC: 25427 AN: 151950 Hom.: 4244 Cov.: 31 AF XY: 0.169 AC XY: 12539 AN XY: 74302

African (AFR) AF: 0.415 AC: 17155 AN: 41340

American (AMR) AF: 0.215 AC: 3282 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3468

East Asian (EAS) AF: 0.158 AC: 812 AN: 5144

South Asian (SAS) AF: 0.108 AC: 520 AN: 4810

European-Finnish (FIN) AF: 0.0654 AC: 694 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0376 AC: 2554 AN: 68002

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.0790 Hom.: 2130

Bravo AF: 0.190

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.31
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
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: rs1861049; hg19: chr4-15482322; COSMIC: COSV67503418;