chr4-15514766-C-T

Variant names:

• chr4-15514766-C-T
• rs2286976
• NM_001378615.1:c.777C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080522.2(CC2D2A):​c.777C>T​(p.His259His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,612,680 control chromosomes in the GnomAD database, including 3,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (396 hom., cov: 33)
  • Exomes 𝑓: 0.035 (2822 hom.)
• Consequence: CC2D2A NM_001080522.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.26
• Publications: 15 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

LOC124900672 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 4-15514766-C-T is Benign according to our data. Variant chr4-15514766-C-T is described in ClinVar as Benign. ClinVar VariationId is 126248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.777C>T	p.His259His	synonymous	Exon 9 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.777C>T	p.His259His	synonymous	Exon 10 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.630C>T	p.His210His	synonymous	Exon 7 of 35	NP_001365546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.777C>T	p.His259His	synonymous	Exon 9 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.777C>T	p.His259His	synonymous	Exon 10 of 38	ENSP00000421809.1
	CC2D2A	ENST00000513811.5	TSL:1	n.957C>T		non_coding_transcript_exon	Exon 9 of 18

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6956 AN: 152070 Hom.: 395 Cov.: 33

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0517

GnomAD2 exomes AF: 0.0534 AC: 13284 AN: 248876 AF XY: 0.0511

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0560

Gnomad EAS exome AF: 0.364

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0520

GnomAD4 exome AF: 0.0353 AC: 51521 AN: 1460492 Hom.: 2822 Cov.: 30 AF XY: 0.0349 AC XY: 25328 AN XY: 726500

African (AFR) AF: 0.0523 AC: 1750 AN: 33458

American (AMR) AF: 0.0212 AC: 947 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0538 AC: 1403 AN: 26088

East Asian (EAS) AF: 0.316 AC: 12522 AN: 39666

South Asian (SAS) AF: 0.0211 AC: 1817 AN: 86130

European-Finnish (FIN) AF: 0.0360 AC: 1920 AN: 53390

Middle Eastern (MID) AF: 0.0871 AC: 502 AN: 5762

European-Non Finnish (NFE) AF: 0.0245 AC: 27217 AN: 1111006

Other (OTH) AF: 0.0571 AC: 3443 AN: 60320

GnomAD4 genome AF: 0.0457 AC: 6948 AN: 152188 Hom.: 396 Cov.: 33 AF XY: 0.0463 AC XY: 3446 AN XY: 74404

African (AFR) AF: 0.0499 AC: 2070 AN: 41518

American (AMR) AF: 0.0290 AC: 443 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.340 AC: 1756 AN: 5170

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4826

European-Finnish (FIN) AF: 0.0370 AC: 391 AN: 10578

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0272 AC: 1849 AN: 68012

Other (OTH) AF: 0.0507 AC: 107 AN: 2110

Alfa AF: 0.0354 Hom.: 680

Bravo AF: 0.0477

Asia WGS AF: 0.179 AC: 622 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0306

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.076
DANN	Benign	0.46
PhyloP100		-2.3
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: rs2286976; hg19: chr4-15516389; COSMIC: COSV67505083; COSMIC: COSV67505083;