4-15601446-G-C

Variant names:

• chr4-15601446-G-C
• rs1134634
• ENST00000634028.2:n.*442G>C

Variant summary

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

The ENST00000634028.2(CC2D2A):​n.*442G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,397,134 control chromosomes in the GnomAD database, including 239,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24886 hom., cov: 33)
  • Exomes 𝑓: 0.58 (214155 hom.)
• Consequence: CC2D2A ENST00000634028.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.946
• Publications: 32 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 4-15601446-G-C is Benign according to our data. Variant chr4-15601446-G-C is described in ClinVar as Benign. ClinVar VariationId is 257382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634028.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.*21G>C		3_prime_UTR	Exon 37 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.*21G>C		3_prime_UTR	Exon 38 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.*21G>C		3_prime_UTR	Exon 35 of 35	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000634028.2	TSL:1	n.*442G>C		non_coding_transcript_exon	Exon 34 of 34	ENSP00000488669.2
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.*21G>C		3_prime_UTR	Exon 37 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.*21G>C		3_prime_UTR	Exon 38 of 38	ENSP00000421809.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86962 AN: 151904 Hom.: 24870 Cov.: 33

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.568

GnomAD2 exomes AF: 0.579 AC: 61752 AN: 106682 AF XY: 0.584

Gnomad AFR exome AF: 0.540

Gnomad AMR exome AF: 0.516

Gnomad ASJ exome AF: 0.635

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.585 AC: 728351 AN: 1245112 Hom.: 214155 Cov.: 21 AF XY: 0.587 AC XY: 354092 AN XY: 603104

African (AFR) AF: 0.540 AC: 15070 AN: 27926

American (AMR) AF: 0.498 AC: 9120 AN: 18316

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 12048 AN: 18878

East Asian (EAS) AF: 0.527 AC: 18817 AN: 35686

South Asian (SAS) AF: 0.646 AC: 33781 AN: 52324

European-Finnish (FIN) AF: 0.554 AC: 25164 AN: 45406

Middle Eastern (MID) AF: 0.641 AC: 2544 AN: 3968

European-Non Finnish (NFE) AF: 0.587 AC: 581677 AN: 991102

Other (OTH) AF: 0.585 AC: 30130 AN: 51506

GnomAD4 genome AF: 0.572 AC: 87016 AN: 152022 Hom.: 24886 Cov.: 33 AF XY: 0.570 AC XY: 42373 AN XY: 74318

African (AFR) AF: 0.546 AC: 22627 AN: 41448

American (AMR) AF: 0.540 AC: 8244 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2278 AN: 3468

East Asian (EAS) AF: 0.502 AC: 2592 AN: 5166

South Asian (SAS) AF: 0.639 AC: 3081 AN: 4824

European-Finnish (FIN) AF: 0.549 AC: 5791 AN: 10550

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 40414 AN: 67972

Other (OTH) AF: 0.564 AC: 1190 AN: 2110

Alfa AF: 0.494 Hom.: 1753

Bravo AF: 0.566

Asia WGS AF: 0.590 AC: 2050 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Meckel syndrome, type 6 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome 9 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.10
DANN	Benign	0.80
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1134634; hg19: chr4-15603069; COSMIC: COSV58010172; COSMIC: COSV58010172;