9-89325666-C-T

Position:

• chr9-89325666-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024077.5(SECISBP2):​c.422C>T​(p.Ala141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,614,108 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (23 hom.)
• Consequence: SECISBP2 NM_024077.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.207

Genes affected

SECISBP2 (HGNC:30972): (SECIS binding protein 2) The protein encoded by this gene is one of the essential components of the machinery involved in co-translational insertion of selenocysteine (Sec) into selenoproteins. Sec is encoded by the UGA codon, which normally signals translation termination. The recoding of UGA as Sec codon requires a Sec insertion sequence (SECIS) element; present in the 3' untranslated regions of eukaryotic selenoprotein mRNAs. This protein specifically binds to the SECIS element, which is stimulated by a Sec-specific translation elongation factor. Mutations in this gene have been associated with reduction in enzymatic activity of type II iodothyronine deiodinase (a selenoprotein) and abnormal thyroid hormone metabolism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

SECISBP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021318197).
• BP6: Variant 9-89325666-C-T is Benign according to our data. Variant chr9-89325666-C-T is described in ClinVar as [Benign]. Clinvar id is 705949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-89325666-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00837 (1275/152252) while in subpopulation AFR AF= 0.0295 (1227/41546). AF 95% confidence interval is 0.0282. There are 15 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SECISBP2	NM_024077.5	c.422C>T	p.Ala141Val	missense_variant	3/17	ENST00000375807.8	NP_076982.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SECISBP2	ENST00000375807.8	c.422C>T	p.Ala141Val	missense_variant	3/17	1	NM_024077.5	ENSP00000364965.3
SECISBP2	ENST00000339901.8	c.203C>T	p.Ala68Val	missense_variant	3/17	1		ENSP00000364959.3
SECISBP2	ENST00000470305.1	n.3467C>T		non_coding_transcript_exon_variant	1/3	1
SECISBP2	ENST00000534113.6	c.218C>T	p.Ala73Val	missense_variant	3/17	2		ENSP00000436650.2

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152134 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00234 AC: 588 AN: 251424 Hom.: 10 AF XY: 0.00155 AC XY: 211 AN XY: 135890

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000936 AC: 1368 AN: 1461856 Hom.: 23 Cov.: 31 AF XY: 0.000788 AC XY: 573 AN XY: 727228

Gnomad4 AFR exome AF: 0.0354

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00837 AC: 1275 AN: 152252 Hom.: 15 Cov.: 33 AF XY: 0.00834 AC XY: 621 AN XY: 74446

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.0101

ESP6500AA AF: 0.0347 AC: 153

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.068	T;D;T
Polyphen		0.65	P;P;.
Vest4		0.24
MVP		0.70
MPC		0.098
ClinPred		0.017	T
GERP RS		2.5
Varity_R		0.056
gMVP		0.040

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: rs62638730; hg19: chr9-91940581;