chr16-30445402-C-T

Variant names:

• chr16-30445402-C-T
• rs199977814
• NM_012248.4:c.326G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012248.4(SEPHS2):​c.326G>A​(p.Ser109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,598,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: SEPHS2 NM_012248.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594
• Publications: 0 publications found

Genes affected

SEPHS2 (HGNC:19686): (selenophosphate synthetase 2) This gene encodes an enzyme that catalyzes the production of monoselenophosphate (MSP) from selenide and ATP. MSP is the selenium donor required for synthesis of selenocysteine (Sec), which is co-translationally incorporated into selenoproteins at in-frame UGA codons that normally signal translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is itself a selenoprotein containing a Sec residue at its active site, suggesting the existence of an autoregulatory mechanism. It is preferentially expressed in tissues implicated in the synthesis of selenoproteins and in sites of blood cell development. A pseudogene for this locus has been identified on chromosome 5. [provided by RefSeq, May 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01179269).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012248.4. 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
	SEPHS2	NM_012248.4	MANE Select	c.326G>A	p.Ser109Asn	missense	Exon 1 of 1	NP_036380.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPHS2	ENST00000478753.5	TSL:6 MANE Select	c.326G>A	p.Ser109Asn	missense	Exon 1 of 1	ENSP00000418669.3	Q99611

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000327 AC: 71 AN: 216946 AF XY: 0.000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.000441

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000550

GnomAD4 exome AF: 0.000540 AC: 781 AN: 1445756 Hom.: 0 Cov.: 31 AF XY: 0.000527 AC XY: 379 AN XY: 718674

African (AFR) AF: 0.0000602 AC: 2 AN: 33246

American (AMR) AF: 0.000234 AC: 10 AN: 42664

Ashkenazi Jewish (ASJ) AF: 0.000391 AC: 10 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 39278

South Asian (SAS) AF: 0.0000826 AC: 7 AN: 84788

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48018

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5718

European-Non Finnish (NFE) AF: 0.000649 AC: 718 AN: 1106646

Other (OTH) AF: 0.000418 AC: 25 AN: 59810

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74510

African (AFR) AF: 0.0000721 AC: 3 AN: 41594

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00172 AC: 14

ExAC AF: 0.000375 AC: 45

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.88
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.59
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.027
Sift	Benign	0.31	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
MVP		0.22
ClinPred		0.011	T
GERP RS		1.6
PromoterAI		-0.065	Neutral
Varity_R		0.054
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199977814; hg19: chr16-30456723;