NM_001378615.1:c.3154G>A

Variant names:

• chr4-15563494-G-A
• rs1055487228
• NM_001378615.1:c.3154G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001378615.1(CC2D2A):​c.3154G>A​(p.Asp1052Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1052G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 1 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

ENSG00000273133 (HGNC:58738):

LOC124900671 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_001378615.1
• PM2: Very rare variant in population databases, with high coverage

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.3154G>A	p.Asp1052Asn	missense	Exon 24 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.3154G>A	p.Asp1052Asn	missense	Exon 25 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.3007G>A	p.Asp1003Asn	missense	Exon 22 of 35	NP_001365546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.3154G>A	p.Asp1052Asn	missense	Exon 24 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.3154G>A	p.Asp1052Asn	missense	Exon 25 of 38	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.3007G>A		non_coding_transcript_exon	Exon 21 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460080 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726116

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111292

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.52	T
Sift4G	Benign	0.46	T
Polyphen		0.98	D
Vest4		0.48
MutPred		0.34		Gain of catalytic residue at D1052 (P = 0.0135)
MVP		0.79
MPC		0.058
ClinPred		0.45	T
GERP RS		5.4
Varity_R		0.13
gMVP		0.69
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1055487228; hg19: chr4-15565117; COSMIC: COSV67503381; COSMIC: COSV67503381;