rs2041673

Positions:

• chr4-15550800-C-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.2182-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,521,954 control chromosomes in the GnomAD database, including 15,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1475 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14293 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.102

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=-0.69).
• BP6: Variant 4-15550800-C-T is Benign according to our data. Variant chr4-15550800-C-T is described in ClinVar as [Benign]. Clinvar id is 126232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.2182-24C>T		intron_variant		ENST00000424120.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.2182-24C>T		intron_variant		5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20544 AN: 152016 Hom.: 1473 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.127 AC: 28865 AN: 226562 Hom.: 2133 AF XY: 0.130 AC XY: 15897 AN XY: 122242

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0276

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.140 AC: 192006 AN: 1369820 Hom.: 14293 Cov.: 27 AF XY: 0.140 AC XY: 94353 AN XY: 672840

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0676

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.0340

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.135 AC: 20571 AN: 152134 Hom.: 1475 Cov.: 32 AF XY: 0.134 AC XY: 9960 AN XY: 74382

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0942

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.114

Alfa AF: 0.146 Hom.: 939

Bravo AF: 0.128

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Meckel syndrome, type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Joubert syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.3
DANN	Benign	0.74

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: rs2041673; hg19: chr4-15552423; COSMIC: COSV67506333;