4-25124081-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive cerebello-cerebral atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SEPSECS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar as Benign. Clinvar id is 130288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-25124081-C-G is described in CliVar 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 rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4 link	c.1356G>C	p.Lys452Asn	missense_variant	Exon 11 of 11	ENST00000382103.7	NP_058651.3	Q9HD40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7 link	c.1356G>C	p.Lys452Asn	missense_variant	Exon 11 of 11	1	NM_016955.4	ENSP00000371535.2		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

GnomAD2 exomes

AF:

0.0662

AC:

16629

AN:

251056

AF XY:

0.0645

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 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

African (AFR)

AF:

0.142

AC:

4742

AN:

33466

American (AMR)

AF:

0.0720

AC:

3220

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

892

AN:

26120

East Asian (EAS)

AF:

0.124

AC:

4914

AN:

39680

South Asian (SAS)

AF:

0.0798

AC:

6879

AN:

86246

European-Finnish (FIN)

AF:

0.0474

AC:

2534

AN:

53408

Middle Eastern (MID)

AF:

0.0553

AC:

319

AN:

5768

European-Non Finnish (NFE)

AF:

0.0437

AC:

48559

AN:

1111718

Other (OTH)

AF:

0.0558

AC:

3370

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3776

7551

11327

15102

18878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1924

3848

5772

7696

9620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0776

AC:

11798

AN:

152108

Hom.:

585

Cov.:

AF XY:

0.0769

AC XY:

5720

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.141

AC:

5843

AN:

41462

American (AMR)

AF:

0.0682

AC:

1041

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3470

East Asian (EAS)

AF:

0.111

AC:

573

AN:

5176

South Asian (SAS)

AF:

0.0908

AC:

438

AN:

4826

European-Finnish (FIN)

AF:

0.0458

AC:

486

AN:

10602

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0451

AC:

3066

AN:

67980

Other (OTH)

AF:

0.0776

AC:

164

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

552

1104

1657

2209

2761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 26, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

1.1

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

Mutation Taster

=76/24

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over