rs1134634

Positions:

• chr4-15601446-G-C
• chr4-15601446-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378615.1(CC2D2A):​c.*21G>C variant causes a 3 prime UTR 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 NM_001378615.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.946

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 257382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15601446-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.*21G>C		3_prime_UTR_variant	37/37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2	c.*21G>C		3_prime_UTR_variant	38/38		NP_001073991.2
CC2D2A	NM_001378617.1	c.*21G>C		3_prime_UTR_variant	35/35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.*21G>C		3_prime_UTR_variant	37/37	5	NM_001378615.1	ENSP00000403465	P1

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

GnomAD3 exomes AF: 0.579 AC: 61752 AN: 106682 Hom.: 17924 AF XY: 0.584 AC XY: 32203 AN XY: 55132

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 SAS exome AF: 0.664

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

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.638

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.585

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

Gnomad4 AFR AF: 0.546

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.502

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.549

Gnomad4 NFE AF: 0.595

Gnomad4 OTH AF: 0.564

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Meckel syndrome, type 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Joubert syndrome 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.10
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1134634; hg19: chr4-15603069; COSMIC: COSV58010172; COSMIC: COSV58010172;