6-118470565-A-G

Variant summary

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

The NM_001042475.3(CEP85L):c.1994T>C(p.Val665Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP85L NM_001042475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42

Genes affected

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

LOC105377971 (HGNC:):

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=0.112083584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP85L	NM_001042475.3	c.1994T>C	p.Val665Ala	missense_variant	11/13	ENST00000368491.8
LOC105377971	XR_001743824.3	n.82+3025A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP85L	ENST00000368491.8	c.1994T>C	p.Val665Ala	missense_variant	11/13	1	NM_001042475.3	P1
CEP85L	ENST00000368488.9	c.2003T>C	p.Val668Ala	missense_variant	12/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452186 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722554

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.1994T>C(p.Val665Ala) variant in CEP85L gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val665Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes database. This variant has not been reported to the ClinVar database. The amino acid change p.Val665Ala in CEP85L is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 665 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Benign	0.0087	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.015	B;.
Vest4		0.076
MutPred		0.12		Loss of ubiquitination at K660 (P = 0.1296);.;
MVP		0.12
MPC		0.098
ClinPred		0.34	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.19

Splicing

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: chr6-118791728;