Genetic Variant SIK1:c.1744+10G>A (chr21-43418250-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173354.5(SIK1):c.1744+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0011 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

SIK1
NM_173354.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.794

Publications

0 publications found

Variant links:

Genes affected

SIK1 (HGNC:11142): (salt inducible kinase 1) This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]

SIK1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 30
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, PanelApp Australia
early myoclonic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SIK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 21-43418250-C-T is Benign according to our data. Variant chr21-43418250-C-T is described in ClinVar as Benign. ClinVar VariationId is 542711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00112 (6/5376) while in subpopulation AMR AF = 0.0132 (2/152). AF 95% confidence interval is 0.00234. There are 2 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173354.5. 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
	SIK1	NM_173354.5	MANE Select	c.1744+10G>A		intron	N/A	NP_775490.2	P57059

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1744+10G>A	intron	N/A	ENSP00000270162.6	P57059
SIK1	ENST00000880890.1		c.1597+10G>A	intron	N/A	ENSP00000550949.1
SIK1	ENST00000880889.1		c.1463-476G>A	intron	N/A	ENSP00000550948.1

Frequencies

GnomAD3 genomes

AF:

0.000714

AC:

AN:

8408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000237

AC:

AN:

244370

AF XY:

0.000181

show subpopulations

Gnomad AFR exome

AF:

0.00306

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00112

AC:

AN:

5376

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

2966

show subpopulations

African (AFR)

AF:

0.00474

AC:

AN:

422

American (AMR)

AF:

0.0132

AC:

AN:

152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

274

East Asian (EAS)

AF:

0.00

AC:

AN:

204

South Asian (SAS)

AF:

0.00

AC:

AN:

740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

3014

Other (OTH)

AF:

0.00556

AC:

AN:

360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000827

AC:

AN:

8466

Hom.:

Cov.:

AF XY:

0.000533

AC XY:

AN XY:

3750

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

3786

American (AMR)

AF:

0.00

AC:

AN:

450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

260

East Asian (EAS)

AF:

0.00

AC:

AN:

188

South Asian (SAS)

AF:

0.00

AC:

AN:

294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

2676

Other (OTH)

AF:

0.00

AC:

AN:

102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000757

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 30 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.79

Mutation Taster

=100/0

polymorphism

(source)

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.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over