chr4-15516648-C-T

Variant names:

• chr4-15516648-C-T
• rs371086728
• NM_001378615.1:c.1041C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001378615.1(CC2D2A):​c.1041C>T​(p.Asp347Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,612,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: CC2D2A NM_001378615.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: -0.369
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 4-15516648-C-T is Benign according to our data. Variant chr4-15516648-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166802.
• BP7: Synonymous conserved (PhyloP=-0.369 with no splicing effect.

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.1041C>T	p.Asp347Asp	synonymous	Exon 11 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.1041C>T	p.Asp347Asp	synonymous	Exon 12 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.894C>T	p.Asp298Asp	synonymous	Exon 9 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.1041C>T	p.Asp347Asp	synonymous	Exon 11 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.1041C>T	p.Asp347Asp	synonymous	Exon 12 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.1221C>T		non_coding_transcript_exon	Exon 11 of 18

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000894 AC: 222 AN: 248248 AF XY: 0.00114

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.000335

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000808

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000670 AC: 978 AN: 1460404 Hom.: 1 Cov.: 30 AF XY: 0.000776 AC XY: 564 AN XY: 726452

African (AFR) AF: 0.000120 AC: 4 AN: 33464

American (AMR) AF: 0.000314 AC: 14 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 26074

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.00294 AC: 253 AN: 86026

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000560 AC: 622 AN: 1111078

Other (OTH) AF: 0.000879 AC: 53 AN: 60328

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74438

African (AFR) AF: 0.000193 AC: 8 AN: 41558

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000616

EpiCase AF: 0.000820

EpiControl AF: 0.00143

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	Joubert syndrome 9 (2)
-	1	-	CC2D2A-related disorder (1)
-	1	-	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		-0.37
Mutation Taster		=99/1	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: rs371086728; hg19: chr4-15518271; COSMIC: COSV67503482; COSMIC: COSV67503482;