18-54938061-T-A

Position:

• chr18-54938061-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025214.3(CCDC68):​c.241A>T​(p.Met81Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC68 NM_025214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.689

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]

CCDC68 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03843656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC68	NM_025214.3	c.241A>T	p.Met81Leu	missense_variant	5/12	ENST00000591504.6	NP_079490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC68	ENST00000591504.6	c.241A>T	p.Met81Leu	missense_variant	5/12	1	NM_025214.3	ENSP00000466690.1
CCDC68	ENST00000432185.5	c.241A>T	p.Met81Leu	missense_variant	3/10	1		ENSP00000413406.1
CCDC68	ENST00000337363.8	c.241A>T	p.Met81Leu	missense_variant	5/12	2		ENSP00000337209.3
CCDC68	ENST00000587148.2	n.622A>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Aug 13, 2021

The c.241A>T (p.M81L) alteration is located in exon 5 (coding exon 3) of the CCDC68 gene. This alteration results from a A to T substitution at nucleotide position 241, causing the methionine (M) at amino acid position 81 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.24
DANN	Benign	0.63
DEOGEN2	Benign	0.0033	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.53	.;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.48	.;N;N
REVEL	Benign	0.016
Sift	Benign	0.62	.;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.010	B;B;B
Vest4		0.19
MutPred		0.22		Gain of catalytic residue at M81 (P = 0.1596);Gain of catalytic residue at M81 (P = 0.1596);Gain of catalytic residue at M81 (P = 0.1596);
MVP		0.085
MPC		0.024
ClinPred		0.96	D
GERP RS		-4.4
Varity_R		0.15
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2044378208; hg19: chr18-52605292;