rs2302566

Positions:

• chr4-25124081-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.06

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]

ACMG classification

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	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	c.1356G>C	p.Lys452Asn	missense_variant	11/11	1	NM_016955.4	P1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11784 AN: 151990 Hom.: 580 Cov.: 32

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

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.: 32 AF XY: 0.0521 AC XY: 37911 AN XY: 727054

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.: 32 AF XY: 0.0769 AC XY: 5720 AN XY: 74378

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 2D Benign:3

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	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.000032	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.065
MutPred		0.49		Loss of methylation at K452 (P = 0.0258);
MPC		0.099
ClinPred		0.028	T
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

Other links and lift over

dbSNP: rs2302566; hg19: chr4-25125703; COSMIC: COSV57206810; COSMIC: COSV57206810;