rs2302566

Variant names:

• chr4-25124081-C-G
• rs2302566
• NM_016955.4:c.1356G>C
• SEPSECS p.Lys452Asn

Your query was ambiguous. Multiple possible variants found:

• chr4-25124081-C-G
• chr4-25124081-C-A
• chr4-25124081-C-T

Variant summary

Our verdict is Benign. The variant received -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:7
• Conservation: PhyloP100: 1.06
• Publications: 16 publications found

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: PanelApp Australia, Broad Center for Mendelian Genomics, 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

ACMG classification

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 ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	NM_016955.4	MANE Select	c.1356G>C	p.Lys452Asn	missense	Exon 11 of 11	NP_058651.3	Q9HD40-1
	SEPSECS	NM_001410714.1		c.1611G>C	p.Lys537Asn	missense	Exon 12 of 12	NP_001397643.1	A0A7P0TA23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.1356G>C	p.Lys452Asn	missense	Exon 11 of 11	ENSP00000371535.2	Q9HD40-1
	SEPSECS	ENST00000358971.7	TSL:1	n.*1154G>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000351857.3	J3KP25
	SEPSECS	ENST00000514585.5	TSL:1	n.*1057G>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000421880.1	Q9HD40-2

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

GnomAD2 exomes AF: 0.0662 AC: 16629 AN: 251056 AF XY: 0.0645

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

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

GnomAD4 genome AF: 0.0776 AC: 11798 AN: 152108 Hom.: 585 Cov.: 32 AF XY: 0.0769 AC XY: 5720 AN XY: 74378

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: 99 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: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0451 AC: 3066 AN: 67980

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0537 Hom.: 196

Bravo AF: 0.0834

Asia WGS AF: 0.121 AC: 423 AN: 3478

EpiCase AF: 0.0475

EpiControl AF: 0.0503

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pontocerebellar hypoplasia type 2D (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Varity_R		0.41
gMVP		0.39
Mutation Taster		=76/24	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2302566;

hg19: chr4-25125703;

COSMIC: COSV57206810;

COSMIC: COSV57206810;