6-109146763-A-G

Position:

• chr6-109146763-A-G

Variant summary

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

The NM_001271852.3(CEP57L1):​c.166A>G​(p.Ile56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,411,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CEP57L1 NM_001271852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.113

Genes affected

CEP57L1 (HGNC:21561): (centrosomal protein 57 like 1) Enables identical protein binding activity. Predicted to be located in cytoplasm and microtubule. Predicted to be active in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

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=0.033180475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP57L1	NM_001271852.3	c.166A>G	p.Ile56Val	missense_variant	3/11	ENST00000517392.6	NP_001258781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP57L1	ENST00000517392.6	c.166A>G	p.Ile56Val	missense_variant	3/11	2	NM_001271852.3	ENSP00000427844

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000113 AC: 16 AN: 1411748 Hom.: 0 Cov.: 30 AF XY: 0.0000128 AC XY: 9 AN XY: 701224

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: 0.0000110

Gnomad4 OTH exome AF: 0.0000515

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

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

Apr 30, 2024

The c.166A>G (p.I56V) alteration is located in exon 5 (coding exon 2) of the CEP57L1 gene. This alteration results from a A to G substitution at nucleotide position 166, causing the isoleucine (I) at amino acid position 56 to be replaced by a valine (V). 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	0.084
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.9
DANN	Benign	0.83
DEOGEN2	Benign	0.012	T;T;T;T;T;.;T;T;T;T;.;T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T;.;T;T;T;T;T;T;T;.;T;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.033	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	.;N;.;.;.;.;.;.;.;.;N;.;.;N
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.41	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.58	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;.;.;.;.;B;.;.;.;B
Vest4		0.14
MutPred		0.16		Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);Gain of ubiquitination at K60 (P = 0.1079);.;Gain of ubiquitination at K60 (P = 0.1079);
MVP		0.20
MPC		0.038
ClinPred		0.020	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs748358761; hg19: chr6-109467966;