rs114335547

Positions:

• chr4-15511227-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378615.1(CC2D2A):​c.541-20T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,581,264 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (89 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27

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]

LOC124900672 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-15511227-T-G is Benign according to our data. Variant chr4-15511227-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 136678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15511227-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00661 (1007/152364) while in subpopulation NFE AF= 0.00983 (669/68036). AF 95% confidence interval is 0.00922. There are 5 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.541-20T>G		intron_variant		ENST00000424120.6	NP_001365544.1
LOC124900672	XR_007058062.1	n.253-3117A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.541-20T>G		intron_variant		5	NM_001378615.1	ENSP00000403465	P1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1007 AN: 152246 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00983

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00686 AC: 1412 AN: 205690 Hom.: 13 AF XY: 0.00677 AC XY: 749 AN XY: 110592

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000333

Gnomad EAS exome AF: 0.000200

Gnomad SAS exome AF: 0.00283

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.00969

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00925 AC: 13212 AN: 1428900 Hom.: 89 Cov.: 30 AF XY: 0.00911 AC XY: 6451 AN XY: 708180

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.000276

Gnomad4 EAS exome AF: 0.0000774

Gnomad4 SAS exome AF: 0.00271

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00754

GnomAD4 genome AF: 0.00661 AC: 1007 AN: 152364 Hom.: 5 Cov.: 33 AF XY: 0.00697 AC XY: 519 AN XY: 74502

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.00983

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00735 Hom.: 0

Bravo AF: 0.00527

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.43
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs114335547; hg19: chr4-15512850;