rs2302565

Variant names:

• chr4-25144685-G-A
• rs2302565
• NM_016955.4:c.1026+89C>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.1026+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 928,910 control chromosomes in the GnomAD database, including 199,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28954 hom., cov: 23)
  • Exomes 𝑓: 0.66 (171021 hom.)
• Consequence: SEPSECS NM_016955.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.551
• Publications: 12 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-25144685-G-A is Benign according to our data. Variant chr4-25144685-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4	c.1026+89C>T		intron_variant	Intron 8 of 10	ENST00000382103.7	NP_058651.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7	c.1026+89C>T		intron_variant	Intron 8 of 10	1	NM_016955.4	ENSP00000371535.2

Frequencies

GnomAD3 genomes AF: 0.621 AC: 91606 AN: 147584 Hom.: 28948 Cov.: 23

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.659 AC: 514964 AN: 781208 Hom.: 171021 AF XY: 0.658 AC XY: 273175 AN XY: 414898

African (AFR) AF: 0.512 AC: 10392 AN: 20308

American (AMR) AF: 0.717 AC: 30700 AN: 42796

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 12556 AN: 21688

East Asian (EAS) AF: 0.543 AC: 19887 AN: 36594

South Asian (SAS) AF: 0.640 AC: 46214 AN: 72164

European-Finnish (FIN) AF: 0.748 AC: 38488 AN: 51426

Middle Eastern (MID) AF: 0.616 AC: 2130 AN: 3458

European-Non Finnish (NFE) AF: 0.668 AC: 330386 AN: 494894

Other (OTH) AF: 0.639 AC: 24211 AN: 37880

GnomAD4 genome AF: 0.620 AC: 91642 AN: 147702 Hom.: 28954 Cov.: 23 AF XY: 0.622 AC XY: 44652 AN XY: 71746

African (AFR) AF: 0.512 AC: 20302 AN: 39666

American (AMR) AF: 0.665 AC: 9700 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2015 AN: 3446

East Asian (EAS) AF: 0.504 AC: 2529 AN: 5014

South Asian (SAS) AF: 0.643 AC: 2937 AN: 4568

European-Finnish (FIN) AF: 0.729 AC: 7286 AN: 9988

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.667 AC: 44826 AN: 67210

Other (OTH) AF: 0.619 AC: 1256 AN: 2028

Alfa AF: 0.649 Hom.: 103050

Bravo AF: 0.613

Asia WGS AF: 0.583 AC: 2028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.54
PhyloP100		-0.55
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs2302565; hg19: chr4-25146307; COSMIC: COSV57204957;