rs1861044

Variant names:

• chr4-15537875-A-G
• rs1861044
• NM_001378615.1:c.1765-24A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378615.1(CC2D2A):​c.1765-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,564,506 control chromosomes in the GnomAD database, including 238,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21471 hom., cov: 31)
  • Exomes 𝑓: 0.55 (217330 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.58
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-15537875-A-G is Benign according to our data. Variant chr4-15537875-A-G is described in ClinVar as Benign. ClinVar VariationId is 126231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.565 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.1765-24A>G		intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.1765-24A>G		intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.1618-24A>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.1765-24A>G		intron	N/A	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.1765-24A>G		intron	N/A	ENSP00000421809.1
	CC2D2A	ENST00000513811.5	TSL:1	n.1945-24A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79942 AN: 151736 Hom.: 21447 Cov.: 31

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.522

GnomAD2 exomes AF: 0.548 AC: 99516 AN: 181456 AF XY: 0.546

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.630

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.341

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.552 AC: 780432 AN: 1412652 Hom.: 217330 Cov.: 35 AF XY: 0.550 AC XY: 384119 AN XY: 697818

African (AFR) AF: 0.459 AC: 14774 AN: 32162

American (AMR) AF: 0.616 AC: 22854 AN: 37082

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 15502 AN: 25274

East Asian (EAS) AF: 0.343 AC: 12663 AN: 36872

South Asian (SAS) AF: 0.506 AC: 40590 AN: 80186

European-Finnish (FIN) AF: 0.576 AC: 29197 AN: 50712

Middle Eastern (MID) AF: 0.486 AC: 2775 AN: 5712

European-Non Finnish (NFE) AF: 0.562 AC: 610385 AN: 1085904

Other (OTH) AF: 0.539 AC: 31692 AN: 58748

GnomAD4 genome AF: 0.527 AC: 80003 AN: 151854 Hom.: 21471 Cov.: 31 AF XY: 0.527 AC XY: 39073 AN XY: 74184

African (AFR) AF: 0.467 AC: 19348 AN: 41392

American (AMR) AF: 0.575 AC: 8768 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2132 AN: 3472

East Asian (EAS) AF: 0.343 AC: 1761 AN: 5134

South Asian (SAS) AF: 0.497 AC: 2391 AN: 4810

European-Finnish (FIN) AF: 0.571 AC: 6012 AN: 10526

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37897 AN: 67958

Other (OTH) AF: 0.526 AC: 1111 AN: 2114

Alfa AF: 0.551 Hom.: 30361

Bravo AF: 0.522

Asia WGS AF: 0.447 AC: 1556 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.010
DANN	Benign	0.61
PhyloP100		-1.6
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: rs1861044; hg19: chr4-15539498; COSMIC: COSV67502071; COSMIC: COSV67502071;