NM_001378615.1:c.3183-8T>C

Variant names:

• chr4-15567369-T-C
• rs13121363
• NM_001378615.1:c.3183-8T>C

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.3183-8T>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 0.71 in 1,600,468 control chromosomes in the GnomAD database, including 404,297 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 0.69 (36510 hom., cov: 31)
  • Exomes 𝑓: 0.71 (367787 hom.)
• Consequence: CC2D2A NM_001378615.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001021
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0100
• Publications: 18 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

LOC124900671 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-15567369-T-C is Benign according to our data. Variant chr4-15567369-T-C is described in ClinVar as Benign. ClinVar VariationId is 126236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.747 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.3183-8T>C		splice_region intron	N/A	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.3183-8T>C		splice_region intron	N/A	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.3036-8T>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.3183-8T>C		splice_region intron	N/A	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.3183-8T>C		splice_region intron	N/A	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.3036-8T>C		splice_region intron	N/A	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104976 AN: 151848 Hom.: 36483 Cov.: 31

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.709 AC: 173646 AN: 244966 AF XY: 0.708

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.792

Gnomad ASJ exome AF: 0.722

Gnomad EAS exome AF: 0.527

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.724

GnomAD4 exome AF: 0.712 AC: 1030645 AN: 1448502 Hom.: 367787 Cov.: 27 AF XY: 0.712 AC XY: 513631 AN XY: 721408

African (AFR) AF: 0.631 AC: 20895 AN: 33126

American (AMR) AF: 0.788 AC: 34516 AN: 43800

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 18796 AN: 25964

East Asian (EAS) AF: 0.562 AC: 22236 AN: 39542

South Asian (SAS) AF: 0.714 AC: 60908 AN: 85266

European-Finnish (FIN) AF: 0.684 AC: 36466 AN: 53342

Middle Eastern (MID) AF: 0.718 AC: 4105 AN: 5720

European-Non Finnish (NFE) AF: 0.718 AC: 790868 AN: 1101822

Other (OTH) AF: 0.699 AC: 41855 AN: 59920

GnomAD4 genome AF: 0.691 AC: 105044 AN: 151966 Hom.: 36510 Cov.: 31 AF XY: 0.689 AC XY: 51218 AN XY: 74290

African (AFR) AF: 0.632 AC: 26195 AN: 41450

American (AMR) AF: 0.758 AC: 11582 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2555 AN: 3470

East Asian (EAS) AF: 0.540 AC: 2785 AN: 5156

South Asian (SAS) AF: 0.707 AC: 3406 AN: 4820

European-Finnish (FIN) AF: 0.678 AC: 7147 AN: 10548

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 48949 AN: 67934

Other (OTH) AF: 0.681 AC: 1435 AN: 2108

Alfa AF: 0.713 Hom.: 30160

Bravo AF: 0.696

Asia WGS AF: 0.643 AC: 2234 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.50
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
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: rs13121363; hg19: chr4-15568992; COSMIC: COSV67502704; COSMIC: COSV67502704;