NM_001378615.1:c.3779C>T

Variant names:

• chr4-15579975-C-T
• rs759726075
• NM_001378615.1:c.3779C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378615.1(CC2D2A):​c.3779C>T​(p.Ser1260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1260S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39293268).

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.3779C>T	p.Ser1260Phe	missense	Exon 30 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.3779C>T	p.Ser1260Phe	missense	Exon 31 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.3632C>T	p.Ser1211Phe	missense	Exon 28 of 35	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.3779C>T	p.Ser1260Phe	missense	Exon 30 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.3779C>T	p.Ser1260Phe	missense	Exon 31 of 38	ENSP00000421809.1
	CC2D2A	ENST00000634028.2	TSL:1	n.3632C>T		non_coding_transcript_exon	Exon 27 of 34	ENSP00000488669.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248886 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Joubert syndrome Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with phenylalanine at codon 1260 of the CC2D2A protein (p.Ser1260Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs759726075, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.57
Sift	Benign	0.10	T
Sift4G	Uncertain	0.048	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.28		Gain of glycosylation at S1260 (P = 0.0093)
MVP		0.91
MPC		0.25
ClinPred		0.94	D
GERP RS		4.5
PromoterAI		0.0094	Neutral
Varity_R		0.16
gMVP		0.80
Mutation Taster		=68/32	polymorphism

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: rs759726075; hg19: chr4-15581598;