4-15559127-G-T

Variant names:

• chr4-15559127-G-T
• rs35309200
• NM_001378615.1:c.2830-38G>T

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.2830-38G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,191,750 control chromosomes in the GnomAD database, including 12,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1425 hom., cov: 32)
  • Exomes 𝑓: 0.14 (11431 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.83
• Publications: 4 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 4-15559127-G-T is Benign according to our data. Variant chr4-15559127-G-T is described in ClinVar as Benign. ClinVar VariationId is 126235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.2830-38G>T		intron	N/A	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.2830-38G>T		intron	N/A	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.2683-38G>T		intron	N/A	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.2830-38G>T		intron	N/A	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.2830-38G>T		intron	N/A	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.2683-38G>T		intron	N/A	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20182 AN: 152082 Hom.: 1423 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.129 AC: 18044 AN: 139968 AF XY: 0.132

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0263

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.145 AC: 150588 AN: 1039550 Hom.: 11431 Cov.: 13 AF XY: 0.145 AC XY: 76213 AN XY: 526716

African (AFR) AF: 0.124 AC: 2937 AN: 23592

American (AMR) AF: 0.0710 AC: 2089 AN: 29426

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3527 AN: 22576

East Asian (EAS) AF: 0.0345 AC: 1162 AN: 33716

South Asian (SAS) AF: 0.136 AC: 9065 AN: 66628

European-Finnish (FIN) AF: 0.161 AC: 7893 AN: 49070

Middle Eastern (MID) AF: 0.0837 AC: 415 AN: 4960

European-Non Finnish (NFE) AF: 0.154 AC: 117462 AN: 763394

Other (OTH) AF: 0.131 AC: 6038 AN: 46188

GnomAD4 genome AF: 0.133 AC: 20208 AN: 152200 Hom.: 1425 Cov.: 32 AF XY: 0.132 AC XY: 9787 AN XY: 74414

African (AFR) AF: 0.123 AC: 5098 AN: 41516

American (AMR) AF: 0.0931 AC: 1424 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.0280 AC: 145 AN: 5174

South Asian (SAS) AF: 0.130 AC: 627 AN: 4826

European-Finnish (FIN) AF: 0.158 AC: 1668 AN: 10590

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10289 AN: 68010

Other (OTH) AF: 0.112 AC: 236 AN: 2110

Alfa AF: 0.100 Hom.: 285

Bravo AF: 0.125

Asia WGS AF: 0.100 AC: 348 AN: 3476

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	6.9
DANN	Benign	0.27
PhyloP100		2.8
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: rs35309200; hg19: chr4-15560750; COSMIC: COSV67503371; COSMIC: COSV67503371;