4-15537121-T-G

Variant names:

• chr4-15537121-T-G
• rs1558572
• NM_001378615.1:c.1764+45T>G

Variant summary

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

The NM_001080522.2(CC2D2A):​c.1764+45T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 1,589,156 control chromosomes in the GnomAD database, including 439,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42648 hom., cov: 32)
  • Exomes 𝑓: 0.74 (396710 hom.)
• Consequence: CC2D2A NM_001080522.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.51
• Publications: 7 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=-0.83).
• BP6: Variant 4-15537121-T-G is Benign according to our data. Variant chr4-15537121-T-G is described in ClinVar as Benign. ClinVar VariationId is 126230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080522.2. 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.1764+45T>G		intron	N/A	NP_001365544.1
	CC2D2A	NM_001080522.2		c.1764+45T>G		intron	N/A	NP_001073991.2
	CC2D2A	NM_001378617.1		c.1617+45T>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.1764+45T>G		intron	N/A	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.1764+45T>G		intron	N/A	ENSP00000421809.1
	CC2D2A	ENST00000513811.5	TSL:1	n.1944+45T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113691 AN: 151988 Hom.: 42592 Cov.: 32

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.733

GnomAD2 exomes AF: 0.753 AC: 173829 AN: 230820 AF XY: 0.748

Gnomad AFR exome AF: 0.758

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.765

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.742 AC: 1066803 AN: 1437050 Hom.: 396710 Cov.: 25 AF XY: 0.740 AC XY: 527220 AN XY: 712660

African (AFR) AF: 0.754 AC: 24859 AN: 32980

American (AMR) AF: 0.791 AC: 33930 AN: 42904

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 19588 AN: 25020

East Asian (EAS) AF: 0.781 AC: 30751 AN: 39350

South Asian (SAS) AF: 0.680 AC: 55908 AN: 82276

European-Finnish (FIN) AF: 0.765 AC: 40184 AN: 52498

Middle Eastern (MID) AF: 0.692 AC: 3912 AN: 5656

European-Non Finnish (NFE) AF: 0.742 AC: 813517 AN: 1096966

Other (OTH) AF: 0.743 AC: 44154 AN: 59400

GnomAD4 genome AF: 0.748 AC: 113806 AN: 152106 Hom.: 42648 Cov.: 32 AF XY: 0.748 AC XY: 55600 AN XY: 74358

African (AFR) AF: 0.759 AC: 31470 AN: 41466

American (AMR) AF: 0.760 AC: 11628 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4146 AN: 5172

South Asian (SAS) AF: 0.674 AC: 3242 AN: 4810

European-Finnish (FIN) AF: 0.768 AC: 8129 AN: 10588

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.738 AC: 50190 AN: 67986

Other (OTH) AF: 0.736 AC: 1555 AN: 2114

Alfa AF: 0.747 Hom.: 14264

Bravo AF: 0.750

Asia WGS AF: 0.739 AC: 2570 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	-0.83
CADD	Benign	0.24
DANN	Benign	0.49
PhyloP100		-1.5
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: rs1558572; hg19: chr4-15538744;