ENST00000503292:c.-32G>A

Variant names:

• chr4-15473242-G-A
• rs183968785
• ENST00000503292.6:c.-32G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000503292.6(CC2D2A):​c.-32G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 152,282 control chromosomes in the GnomAD database, including 6 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 0.0062 (6 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CC2D2A ENST00000503292.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.952
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-15473242-G-A is Benign according to our data. Variant chr4-15473242-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 347751.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00624 (950/152282) while in subpopulation NFE AF = 0.00963 (655/68018). AF 95% confidence interval is 0.00902. There are 6 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000503292.6. 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.-18-2673G>A		intron	N/A	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.-32G>A		5_prime_UTR	Exon 2 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_020785.2		c.-32G>A		5_prime_UTR	Exon 2 of 7	NP_065836.2	Q9P2K1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000503292.6	TSL:1	c.-32G>A		5_prime_UTR	Exon 2 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000503658.2	TSL:1	c.-32G>A		5_prime_UTR	Exon 2 of 7	ENSP00000426846.1	Q9P2K1-5
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.-18-2673G>A		intron	N/A	ENSP00000403465.1	Q9P2K1-4

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152164 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00519

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00963

Gnomad OTH AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152282 Hom.: 6 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74460

African (AFR) AF: 0.00204 AC: 85 AN: 41568

American (AMR) AF: 0.00661 AC: 101 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00519 AC: 55 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68018

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00682 Hom.: 1

Bravo AF: 0.00582

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 9 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.54
DANN	Benign	0.64
PhyloP100		-0.95
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs183968785; hg19: chr4-15474866;