NM_001378615.1:c.3771+1638A>G

Variant names:

• chr4-15575964-A-G
• rs12649803
• NM_001378615.1:c.3771+1638A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378615.1(CC2D2A):​c.3771+1638A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 152,046 control chromosomes in the GnomAD database, including 23,532 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (23532 hom., cov: 32)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.615
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.652 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.3771+1638A>G		intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.3771+1638A>G		intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.3624+1638A>G		intron	N/A	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.3771+1638A>G		intron	N/A	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.3771+1638A>G		intron	N/A	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.3624+1638A>G		intron	N/A	ENSP00000488669.2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84103 AN: 151928 Hom.: 23520 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.553 AC: 84143 AN: 152046 Hom.: 23532 Cov.: 32 AF XY: 0.553 AC XY: 41103 AN XY: 74342

African (AFR) AF: 0.493 AC: 20438 AN: 41474

American (AMR) AF: 0.663 AC: 10129 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2013 AN: 3470

East Asian (EAS) AF: 0.512 AC: 2643 AN: 5164

South Asian (SAS) AF: 0.575 AC: 2772 AN: 4820

European-Finnish (FIN) AF: 0.518 AC: 5478 AN: 10578

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.569 AC: 38656 AN: 67954

Other (OTH) AF: 0.568 AC: 1200 AN: 2114

Alfa AF: 0.566 Hom.: 61275

Bravo AF: 0.566

Asia WGS AF: 0.541 AC: 1881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.18
DANN	Benign	0.21
PhyloP100		-0.61
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: rs12649803; hg19: chr4-15577587;