4-15473476-A-G

Variant names:

• chr4-15473476-A-G
• rs10022530
• NM_001378615.1:c.-18-2439A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378615.1(CC2D2A):​c.-18-2439A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 152,176 control chromosomes in the GnomAD database, including 54,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.85 (54892 hom., cov: 32)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.327
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-15473476-A-G is Benign according to our data. Variant chr4-15473476-A-G is described in ClinVar as [Benign]. Clinvar id is 1238142.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.-18-2439A>G		intron_variant	Intron 1 of 36	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.-18-2439A>G		intron_variant	Intron 1 of 36	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128961 AN: 152058 Hom.: 54855 Cov.: 32

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.844

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.848 AC: 129060 AN: 152176 Hom.: 54892 Cov.: 32 AF XY: 0.848 AC XY: 63105 AN XY: 74420

African (AFR) AF: 0.799 AC: 33152 AN: 41470

American (AMR) AF: 0.835 AC: 12761 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2970 AN: 3472

East Asian (EAS) AF: 0.974 AC: 5038 AN: 5172

South Asian (SAS) AF: 0.770 AC: 3718 AN: 4828

European-Finnish (FIN) AF: 0.890 AC: 9440 AN: 10602

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.869 AC: 59085 AN: 68026

Other (OTH) AF: 0.844 AC: 1784 AN: 2114

Alfa AF: 0.863 Hom.: 6720

Bravo AF: 0.846

Asia WGS AF: 0.837 AC: 2913 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 28, 2020

GeneDx

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	-0.94
CADD	Benign	0.83
DANN	Benign	0.71
PhyloP100		-0.33
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: rs10022530; hg19: chr4-15475100;