rs548640382

Variant names:

• chr21-43417737-C-T
• rs548640382
• NM_173354.5:c.1782G>A
• SIK1 p.Thr594Thr

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_173354.5(SIK1):​c.1782G>A​(p.Thr594Thr) variant causes a synonymous 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000030 (4 hom.)
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 0 publications found

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: PanelApp Australia, Orphanet, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 21-43417737-C-T is Benign according to our data. Variant chr21-43417737-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000298 (8/268560) while in subpopulation EAS AF = 0.000282 (2/7098). AF 95% confidence interval is 0.0000493. There are 4 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 8 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.1782G>A	p.Thr594Thr	synonymous	Exon 13 of 14	NP_775490.2	P57059

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1782G>A	p.Thr594Thr	synonymous	Exon 13 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1635G>A	p.Thr545Thr	synonymous	Exon 12 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1500G>A	p.Thr500Thr	synonymous	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes AF: 0.0000225 AC: 1 AN: 44490 Hom.: 0 Cov.: 4

Gnomad AFR AF: 0.0000506

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: 0.000439 AC: 89 AN: 202582 AF XY: 0.000627

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.0000298 AC: 8 AN: 268560 Hom.: 4 Cov.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134460

African (AFR) AF: 0.00 AC: 0 AN: 12032

American (AMR) AF: 0.00 AC: 0 AN: 2742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5780

East Asian (EAS) AF: 0.000282 AC: 2 AN: 7098

South Asian (SAS) AF: 0.00 AC: 0 AN: 18354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1204

European-Non Finnish (NFE) AF: 0.0000296 AC: 6 AN: 203034

Other (OTH) AF: 0.00 AC: 0 AN: 13220

GnomAD4 genome AF: 0.0000225 AC: 1 AN: 44490 Hom.: 0 Cov.: 4 AF XY: 0.0000484 AC XY: 1 AN XY: 20656

African (AFR) AF: 0.0000506 AC: 1 AN: 19760

American (AMR) AF: 0.00 AC: 0 AN: 2586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1244

East Asian (EAS) AF: 0.00 AC: 0 AN: 816

South Asian (SAS) AF: 0.00 AC: 0 AN: 1234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 17026

Other (OTH) AF: 0.00 AC: 0 AN: 564

Alfa AF: 0.0000474 Hom.: 0

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.5
DANN	Benign	0.90
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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.

Other links and lift over

dbSNP: rs548640382;

hg19: chr21-44837617;