4-15567369-T-C

Variant names:

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

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.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

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]

LOC124900671 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 126236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15567369-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.3183-8T>C		splice_region_variant, intron_variant	Intron 24 of 36	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2	c.3183-8T>C		splice_region_variant, intron_variant	Intron 25 of 37		NP_001073991.2
CC2D2A	NM_001378617.1	c.3036-8T>C		splice_region_variant, intron_variant	Intron 22 of 34		NP_001365546.1
LOC124900671	XR_007058061.1	n.131-3173A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.3183-8T>C		splice_region_variant, intron_variant	Intron 24 of 36	5	NM_001378615.1	ENSP00000403465.1

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

GnomAD3 exomes AF: 0.709 AC: 173646 AN: 244966 Hom.: 62101 AF XY: 0.708 AC XY: 94120 AN XY: 132998

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 SAS exome AF: 0.719

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

Gnomad4 AFR exome AF: 0.631

Gnomad4 AMR exome AF: 0.788

Gnomad4 ASJ exome AF: 0.724

Gnomad4 EAS exome AF: 0.562

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.718

Gnomad4 OTH exome AF: 0.699

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

Gnomad4 AFR AF: 0.632

Gnomad4 AMR AF: 0.758

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.707

Gnomad4 FIN AF: 0.678

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.681

Alfa AF: 0.713 Hom.: 26949

Bravo AF: 0.696

Asia WGS AF: 0.643 AC: 2234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 6 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Joubert syndrome 9 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs13121363; hg19: chr4-15568992; COSMIC: COSV67502704; COSMIC: COSV67502704;