rs61734948

Variant names:

• chr4-15570411-G-A
• rs61734948
• NM_001378615.1:c.3509G>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.3509G>A​(p.Arg1170Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,599,478 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (13 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.23
• Publications: 5 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

LOC124900671 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009373516).
• BP6: Variant 4-15570411-G-A is Benign according to our data. Variant chr4-15570411-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126240.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 = 0.00609 (927/152302) while in subpopulation AFR AF = 0.0213 (886/41562). AF 95% confidence interval is 0.0202. There are 12 homozygotes in GnomAd4. There are 440 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.3509G>A	p.Arg1170Lys	missense	Exon 28 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.3509G>A	p.Arg1170Lys	missense	Exon 29 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.3362G>A	p.Arg1121Lys	missense	Exon 26 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.3509G>A	p.Arg1170Lys	missense	Exon 28 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.3509G>A	p.Arg1170Lys	missense	Exon 29 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.3362G>A		non_coding_transcript_exon	Exon 25 of 34	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152184 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00155 AC: 372 AN: 240108 AF XY: 0.00131

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.000777

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000639 AC: 925 AN: 1447176 Hom.: 13 Cov.: 28 AF XY: 0.000544 AC XY: 391 AN XY: 718302

African (AFR) AF: 0.0236 AC: 787 AN: 33300

American (AMR) AF: 0.000842 AC: 37 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.000131 AC: 11 AN: 84096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5730

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102030

Other (OTH) AF: 0.00120 AC: 72 AN: 59812

GnomAD4 genome AF: 0.00609 AC: 927 AN: 152302 Hom.: 12 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74470

African (AFR) AF: 0.0213 AC: 886 AN: 41562

American (AMR) AF: 0.00189 AC: 29 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00248 Hom.: 7

Bravo AF: 0.00674

ESP6500AA AF: 0.0162 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00184 AC: 222

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.018	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.76
MVP		0.91
MPC		0.27
ClinPred		0.035	T
GERP RS		5.7
Varity_R		0.44
gMVP		0.46
Mutation Taster		=100/0	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: rs61734948; hg19: chr4-15572034;