18-54919327-G-A

Position:

• chr18-54919327-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025214.3(CCDC68):​c.733C>T​(p.His245Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC68 NM_025214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24116078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC68	NM_025214.3	c.733C>T	p.His245Tyr	missense_variant	9/12	ENST00000591504.6	NP_079490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC68	ENST00000591504.6	c.733C>T	p.His245Tyr	missense_variant	9/12	1	NM_025214.3	ENSP00000466690.1
CCDC68	ENST00000432185.5	c.733C>T	p.His245Tyr	missense_variant	7/10	1		ENSP00000413406.1
CCDC68	ENST00000337363.8	c.733C>T	p.His245Tyr	missense_variant	9/12	2		ENSP00000337209.3
CCDC68	ENST00000592040.5	c.334C>T	p.His112Tyr	missense_variant	4/8	3		ENSP00000466731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 24, 2024

The c.733C>T (p.H245Y) alteration is located in exon 9 (coding exon 7) of the CCDC68 gene. This alteration results from a C to T substitution at nucleotide position 733, causing the histidine (H) at amino acid position 245 to be replaced by a tyrosine (Y). 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	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	.;T;.
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	.;D;D
REVEL	Benign	0.080
Sift	Uncertain	0.0020	.;D;D
Sift4G	Benign	0.088	T;T;T
Polyphen		0.13	B;B;B
Vest4		0.50
MutPred		0.30		Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);Loss of disorder (P = 0.0311);
MVP		0.13
MPC		0.047
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.41
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr18-52586558;