4-15480853-A-G

Variant names:

• chr4-15480853-A-G
• rs10000250
• NM_001378615.1:c.247+26A>G

Variant summary

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

The NM_001378615.1(CC2D2A):​c.247+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 1,601,896 control chromosomes in the GnomAD database, including 602,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55233 hom., cov: 29)
  • Exomes 𝑓: 0.87 (547535 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.307
• Publications: 9 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=-0.89).
• BP6: Variant 4-15480853-A-G is Benign according to our data. Variant chr4-15480853-A-G is described in ClinVar as Benign. ClinVar VariationId is 126233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.247+26A>G		intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.247+26A>G		intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.100+26A>G		intron	N/A	NP_001365546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.247+26A>G		intron	N/A	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.247+26A>G		intron	N/A	ENSP00000421809.1
	CC2D2A	ENST00000503658.2	TSL:1	c.353+26A>G		intron	N/A	ENSP00000426846.1

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129250 AN: 151774 Hom.: 55188 Cov.: 29

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.847

GnomAD2 exomes AF: 0.860 AC: 205254 AN: 238546 AF XY: 0.858

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.979

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.871

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.868 AC: 1258856 AN: 1450004 Hom.: 547535 Cov.: 37 AF XY: 0.866 AC XY: 623367 AN XY: 720178

African (AFR) AF: 0.812 AC: 26829 AN: 33038

American (AMR) AF: 0.840 AC: 36176 AN: 43056

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 22065 AN: 25652

East Asian (EAS) AF: 0.980 AC: 38699 AN: 39490

South Asian (SAS) AF: 0.779 AC: 66119 AN: 84874

European-Finnish (FIN) AF: 0.892 AC: 47365 AN: 53082

Middle Eastern (MID) AF: 0.866 AC: 4940 AN: 5702

European-Non Finnish (NFE) AF: 0.873 AC: 964982 AN: 1105334

Other (OTH) AF: 0.865 AC: 51681 AN: 59776

GnomAD4 genome AF: 0.852 AC: 129359 AN: 151892 Hom.: 55233 Cov.: 29 AF XY: 0.852 AC XY: 63242 AN XY: 74250

African (AFR) AF: 0.809 AC: 33493 AN: 41386

American (AMR) AF: 0.836 AC: 12755 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2979 AN: 3468

East Asian (EAS) AF: 0.973 AC: 4992 AN: 5130

South Asian (SAS) AF: 0.774 AC: 3722 AN: 4810

European-Finnish (FIN) AF: 0.891 AC: 9410 AN: 10560

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.870 AC: 59111 AN: 67980

Other (OTH) AF: 0.847 AC: 1783 AN: 2104

Alfa AF: 0.870 Hom.: 74174

Bravo AF: 0.850

Asia WGS AF: 0.839 AC: 2920 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.58
PhyloP100		0.31
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: rs10000250; hg19: chr4-15482477;