Genetic Variant SECISBP2:c.1212+29G>A (chr9-89338609-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_024077.5(SECISBP2):c.1212+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SECISBP2
NM_024077.5 intron

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.840

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

thyroid hormone metabolism, abnormal 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
short stature-delayed bone age due to thyroid hormone metabolism deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SECISBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-89338609-G-A is Pathogenic according to our data. Variant chr9-89338609-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2921.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SECISBP2	NM_024077.5	MANE Select	c.1212+29G>A	intron	N/A	NP_076982.3
SECISBP2	NM_001282688.2		c.1209+29G>A	intron	N/A	NP_001269617.1
SECISBP2	NM_001354697.2		c.1098+29G>A	intron	N/A	NP_001341626.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SECISBP2	ENST00000375807.8	TSL:1 MANE Select	c.1212+29G>A	intron	N/A	ENSP00000364965.3
SECISBP2	ENST00000339901.8	TSL:1	c.993+29G>A	intron	N/A	ENSP00000364959.3
SECISBP2	ENST00000960321.1		c.1212+29G>A	intron	N/A	ENSP00000630380.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454284

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33118

American (AMR)

AF:

0.00

AC:

AN:

44260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

85114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4836

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109206

Other (OTH)

AF:

0.0000166

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thyroid hormone metabolism, abnormal 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.39

PhyloP100

-0.84

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.84

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over