rs2302566

Positions:

chr4-25124081-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016955.4(SEPSECS):c.1356G>C(p.Lys452Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0541 in 1,613,602 control chromosomes in the GnomAD database, including 2,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 585 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2407 hom. )

Consequence

SEPSECS
NM_016955.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.06

Variant links:

Genes affected

SEPSECS (HGNC:30605): (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase) The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

SEPSECS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024281442).

BP6

Variant 4-25124081-C-G is Benign according to our data. Variant chr4-25124081-C-G is described in ClinVar as [Benign]. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPSECS	NM_016955.4 linkuse as main transcript	c.1356G>C	p.Lys452Asn	missense_variant	11/11	ENST00000382103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPSECS	ENST00000382103.7 linkuse as main transcript	c.1356G>C	p.Lys452Asn	missense_variant	11/11	1	NM_016955.4	P1	Q9HD40-1

Frequencies

GnomAD3 genomes

AF:

0.0775

AC:

11784

AN:

151990

Hom.:

580

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.0684

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.0913

Gnomad FIN

AF:

0.0458

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0451

Gnomad OTH

AF:

0.0722

GnomAD3 exomes

AF:

0.0662

AC:

16629

AN:

251056

Hom.:

723

AF XY:

0.0645

AC XY:

8749

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.0727

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.126

Gnomad SAS exome

AF:

0.0791

Gnomad FIN exome

AF:

0.0499

Gnomad NFE exome

AF:

0.0455

Gnomad OTH exome

AF:

0.0655

GnomAD4 exome

AF:

0.0516

AC:

75429

AN:

1461494

Hom.:

2407

Cov.:

AF XY:

0.0521

AC XY:

37911

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.0720

Gnomad4 ASJ exome

AF:

0.0342

Gnomad4 EAS exome

AF:

0.124

Gnomad4 SAS exome

AF:

0.0798

Gnomad4 FIN exome

AF:

0.0474

Gnomad4 NFE exome

AF:

0.0437

Gnomad4 OTH exome

AF:

0.0558

GnomAD4 genome

AF:

0.0776

AC:

11798

AN:

152108

Hom.:

585

Cov.:

AF XY:

0.0769

AC XY:

5720

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.0682

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.111

Gnomad4 SAS

AF:

0.0908

Gnomad4 FIN

AF:

0.0458

Gnomad4 NFE

AF:

0.0451

Gnomad4 OTH

AF:

0.0776

Alfa

AF:

0.0537

Hom.:

196

Bravo

AF:

0.0834

TwinsUK

AF:

0.0394

AC:

146

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.138

AC:

607

ESP6500EA

AF:

0.0457

AC:

393

ExAC

AF:

0.0667

AC:

8099

Asia WGS

AF:

0.121

AC:

423

AN:

3478

EpiCase

AF:

0.0475

EpiControl

AF:

0.0503

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 2D

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

0.11

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

0.000032

P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.41

Sift

Benign

0.18

Sift4G

Benign

0.27

Polyphen

0.99

Vest4

0.065

MutPred

0.49

Loss of methylation at K452 (P = 0.0258);

MPC

0.099

ClinPred

0.028

GERP RS

1.1

Varity_R

0.41

gMVP

0.39

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