18-54907861-T-C

Position:

• chr18-54907861-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025214.3(CCDC68):​c.875A>G​(p.Asn292Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC68 NM_025214.3 missense, splice_region
• Scores: Splicing: ADA: 0.8920
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

Genes affected

CCDC68 (HGNC:24350): (coiled-coil domain containing 68) Involved in microtubule anchoring at centrosome and protein localization. Located in centriole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC68	NM_025214.3	c.875A>G	p.Asn292Ser	missense_variant, splice_region_variant	11/12	ENST00000591504.6	NP_079490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC68	ENST00000591504.6	c.875A>G	p.Asn292Ser	missense_variant, splice_region_variant	11/12	1	NM_025214.3	ENSP00000466690.1
CCDC68	ENST00000432185.5	c.875A>G	p.Asn292Ser	missense_variant, splice_region_variant	9/10	1		ENSP00000413406.1
CCDC68	ENST00000337363.8	c.875A>G	p.Asn292Ser	missense_variant, splice_region_variant	11/12	2		ENSP00000337209.3
CCDC68	ENST00000592040.5	c.476A>G	p.Asn159Ser	missense_variant, splice_region_variant	6/8	3		ENSP00000466731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

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

Nov 25, 2024

The c.875A>G (p.N292S) alteration is located in exon 11 (coding exon 9) of the CCDC68 gene. This alteration results from a A to G substitution at nucleotide position 875, causing the asparagine (N) at amino acid position 292 to be replaced by a serine (S). 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	0.62
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	.;T;.
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.1	.;D;D
REVEL	Benign	0.092
Sift	Uncertain	0.028	.;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.51	P;P;P
Vest4		0.81
MutPred		0.15		Gain of phosphorylation at N292 (P = 0.0559);Gain of phosphorylation at N292 (P = 0.0559);Gain of phosphorylation at N292 (P = 0.0559);
MVP		0.43
MPC		0.062
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.28
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-52575092; COSMIC: COSV61604434;