2-117939031-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019044.5(CCDC93):c.1603G>A(p.Glu535Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000071 in 1,408,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: CCDC93 NM_019044.5 missense, splice_region
• Scores: Splicing: ADA: 0.9539
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

Genes affected

CCDC93 (HGNC:25611): (coiled-coil domain containing 93) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC93	NM_019044.5	c.1603G>A	p.Glu535Lys	missense_variant, splice_region_variant	20/24	ENST00000376300.7
CCDC93	XM_011511359.2	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	20/24
CCDC93	XM_011511361.1	c.1315G>A	p.Glu439Lys	missense_variant, splice_region_variant	19/23
CCDC93	XM_047444816.1	c.1204G>A	p.Glu402Lys	missense_variant, splice_region_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC93	ENST00000376300.7	c.1603G>A	p.Glu535Lys	missense_variant, splice_region_variant	20/24	1	NM_019044.5	P4
CCDC93	ENST00000319432.9	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	20/24	5		A1
CCDC93	ENST00000466171.1	n.247G>A		splice_region_variant, non_coding_transcript_exon_variant	3/4	3
CCDC93	ENST00000437999.5	c.*243G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	7/11	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000710 AC: 10 AN: 1408136 Hom.: 0 Cov.: 23 AF XY: 0.00000995 AC XY: 7 AN XY: 703464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000845

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.1603G>A (p.E535K) alteration is located in exon 20 (coding exon 20) of the CCDC93 gene. This alteration results from a G to A substitution at nucleotide position 1603, causing the glutamic acid (E) at amino acid position 535 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.55		Gain of ubiquitination at E535 (P = 0.0198);.;
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.82
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

Publications

LitVar

Other links and lift over

dbSNP: rs969718782; hg19: chr2-118696607;