Variant 2-138552663-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001001664.3(SPOPL):c.462G>C(p.Lys154Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 152,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Consequence

SPOPL
NM_001001664.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Variant links:

Genes affected

SPOPL (HGNC:27934): (speckle type BTB/POZ protein like) Predicted to enable ubiquitin protein ligase binding activity. Involved in negative regulation of protein ubiquitination and proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

SPOPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOPL	NM_001001664.3 linkuse as main transcript	c.462G>C	p.Lys154Asn	missense_variant	5/11	ENST00000280098.9	NP_001001664.1	Q6IQ16
SPOPL	XM_047444115.1 linkuse as main transcript	c.140G>C	p.Ser47Thr	missense_variant	3/10		XP_047300071.1
SPOPL	XM_047444116.1 linkuse as main transcript	c.140G>C	p.Ser47Thr	missense_variant	3/10		XP_047300072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOPL	ENST00000280098.9 linkuse as main transcript	c.462G>C	p.Lys154Asn	missense_variant	5/11	1	NM_001001664.3	ENSP00000280098.4		Q6IQ16
SPOPL	ENST00000420679.1 linkuse as main transcript	n.462G>C		non_coding_transcript_exon_variant	4/11	5		ENSP00000396006.1		F8WD02

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249628

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2024

The c.462G>C (p.K154N) alteration is located in exon 5 (coding exon 4) of the SPOPL gene. This alteration results from a G to C substitution at nucleotide position 462, causing the lysine (K) at amino acid position 154 to be replaced by an asparagine (N). 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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.19

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Polyphen

0.90

Vest4

0.77

MutPred

0.53

Loss of ubiquitination at K154 (P = 0.0283);

MVP

0.77

MPC

0.68

ClinPred

0.96

GERP RS

3.5

Varity_R

0.66

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over