rs1344011

Positions:

• chr18-54937957-C-A
• chr18-54937957-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025214.3(CCDC68):​c.345G>T​(p.Lys115Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to 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: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC68	NM_025214.3	c.345G>T	p.Lys115Asn	missense_variant, splice_region_variant	5/12	ENST00000591504.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC68	ENST00000591504.6	c.345G>T	p.Lys115Asn	missense_variant, splice_region_variant	5/12	1	NM_025214.3	P1
CCDC68	ENST00000432185.5	c.345G>T	p.Lys115Asn	missense_variant, splice_region_variant	3/10	1		P1
CCDC68	ENST00000337363.8	c.345G>T	p.Lys115Asn	missense_variant, splice_region_variant	5/12	2		P1
CCDC68	ENST00000587148.2	n.726G>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	0.0017	P;P;P
PrimateAI	Uncertain	0.67	T
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.23		Loss of ubiquitination at K115 (P = 0.0161);Loss of ubiquitination at K115 (P = 0.0161);Loss of ubiquitination at K115 (P = 0.0161);
MVP		0.76
MPC		0.21
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.72
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1344011; hg19: chr18-52605188;