chr4-15597431-TCAGA-T

Variant names:

• chr4-15597431-TCAGA-T
• rs797045437
• NM_001378615.1:c.4465_4468delGACA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2_SupportingPP5_Strong

The NM_001378615.1(CC2D2A):c.4465_4468delGACA (p.Asp1489LysfsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.0000167 (AC=26) in the gnomAD database across 1,553,158 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000379. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.44). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CC2D2A NM_001378615.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.44
• Publications: 1 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 35 of 37) at amino acid 1489 of 1620, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~1502 amino acids (118 amino acids lost).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000379 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (10/10 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CC2D2A NM_001378615.1	MANE Select	c.4465_4468delGACA p.Asp1489LysfsTer15	frameshift	Exon 35 of 37	Prot: NP_001365544.1 UniProt:
	CC2D2A NM_001080522.2		c.4465_4468delGACA p.Asp1489LysfsTer15	frameshift	Exon 36 of 38	Prot: NP_001073991.2 UniProt:
	CC2D2A NM_001378617.1		c.4318_4321delGACA p.Asp1440LysfsTer15	frameshift	Exon 33 of 35	Prot: NP_001365546.1 UniProt:

CC2D2A NM_001378615.1

MANE Select

HGVSc / HGVSpc.4465_4468delGACAp.Asp1489LysfsTer15

Exon rankExon 35 of 37

frameshift

Prot: NP_001365544.1UniProt: Q9P2K1-4

CC2D2A NM_001080522.2

HGVSc / HGVSpc.4465_4468delGACAp.Asp1489LysfsTer15

Exon rankExon 36 of 38

frameshift

Prot: NP_001073991.2UniProt: Q9P2K1-4

CC2D2A NM_001378617.1

HGVSc / HGVSpc.4318_4321delGACAp.Asp1440LysfsTer15

Exon rankExon 33 of 35

frameshift

Prot: NP_001365546.1UniProt: H0Y941

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CC2D2A ENST00000424120.6	TSL:5MANE Select	c.4465_4468delGACA p.Asp1489LysfsTer15	frameshift	Exon 35 of 37	Prot: ENSP00000403465.1 UniProt:
	CC2D2A ENST00000503292.6	TSL:1	c.4465_4468delGACA p.Asp1489LysfsTer15	frameshift	Exon 36 of 38	Prot: ENSP00000421809.1 UniProt:
	CC2D2A ENST00000634028.2	TSL:1	n.*23_*26delGACA	3_prime_UTR	Exon 32 of 34	Prot: ENSP00000488669.2 UniProt:

CC2D2A ENST00000424120.6

TSL:5MANE Select

HGVSc / HGVSpc.4465_4468delGACAp.Asp1489LysfsTer15

Exon rankExon 35 of 37

frameshift

Prot: ENSP00000403465.1UniProt: Q9P2K1-4

CC2D2A ENST00000503292.6

TSL:1

HGVSc / HGVSpc.4465_4468delGACAp.Asp1489LysfsTer15

Exon rankExon 36 of 38

frameshift

Prot: ENSP00000421809.1UniProt: Q9P2K1-4

CC2D2A ENST00000634028.2

TSL:1

HGVSc / HGVSpn.*23_*26delGACA

Exon rankExon 32 of 34

3_prime_UTR

Prot: ENSP00000488669.2UniProt: A0A0J9YY35

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000394	AC:6	Hom:0	AN:152176	Cov:32
GnomAD2 exomes	AF: 0.0000618	AC:10	Hom:	AN:161732	Cov:
GnomAD4 exome	AF: 0.0000143	AC:20	Hom:0	AN:1400982	Cov:
GnomAD4 genome	AF: 0.0000394	AC:6	Hom:0	AN:152176	Cov:32
TOPMed (Bravo)	AF: 0.0000340	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:1	Hom:0	AN:16840	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122158	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41956	0.00	0	66882
SCHEMA(Schizophrenia)	0.0000418	4	95688	0.0000475	8	168430

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Joubert syndrome 9 (2)
2	-	-	Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5436837:COACH syndrome 2;C5676970:Retinitis pigmentosa 93 (2)
1	-	-	Autosomal recessive CC2D2A-related disorders (1)
1	-	-	CC2D2A-related disorder (1)
1	-	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	9.4

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs797045437;

hg19: chr4-15599054;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar