rs62000428

Variant names:

• chr4-15514710-G-A
• rs62000428
• NM_001378615.1:c.721G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378615.1(CC2D2A):​c.721G>A​(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,530,718 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (10 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.05
• Publications: 6 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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

LOC124900672 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004833162).
• BP6: Variant 4-15514710-G-A is Benign according to our data. Variant chr4-15514710-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00686 (1045/152298) while in subpopulation AFR AF = 0.0236 (981/41548). AF 95% confidence interval is 0.0224. There are 16 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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.721G>A	p.Glu241Lys	missense	Exon 9 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.721G>A	p.Glu241Lys	missense	Exon 10 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.574G>A	p.Glu192Lys	missense	Exon 7 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.721G>A	p.Glu241Lys	missense	Exon 9 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.721G>A	p.Glu241Lys	missense	Exon 10 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.901G>A		non_coding_transcript_exon	Exon 9 of 18

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1038 AN: 152180 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00197 AC: 434 AN: 220178 AF XY: 0.00144

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000351

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000771 AC: 1063 AN: 1378420 Hom.: 10 Cov.: 30 AF XY: 0.000687 AC XY: 466 AN XY: 678214

African (AFR) AF: 0.0247 AC: 775 AN: 31360

American (AMR) AF: 0.00203 AC: 75 AN: 36922

Ashkenazi Jewish (ASJ) AF: 0.000380 AC: 9 AN: 23668

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.000151 AC: 11 AN: 72724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51662

Middle Eastern (MID) AF: 0.00148 AC: 8 AN: 5406

European-Non Finnish (NFE) AF: 0.0000753 AC: 80 AN: 1062554

Other (OTH) AF: 0.00186 AC: 105 AN: 56384

GnomAD4 genome AF: 0.00686 AC: 1045 AN: 152298 Hom.: 16 Cov.: 33 AF XY: 0.00658 AC XY: 490 AN XY: 74478

African (AFR) AF: 0.0236 AC: 981 AN: 41548

American (AMR) AF: 0.00216 AC: 33 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00277 Hom.: 10

Bravo AF: 0.00808

ESP6500AA AF: 0.0220 AC: 84

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00229 AC: 277

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Uncertain	0.018	D
Polyphen		0.70	P
Vest4		0.50
MVP		0.41
MPC		0.073
ClinPred		0.023	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.52
Mutation Taster		=97/3	polymorphism

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: rs62000428; hg19: chr4-15516333; COSMIC: COSV99067342; COSMIC: COSV99067342;