rs376554812

Variant names:

• chr21-43417644-C-A
• rs376554812
• NM_173354.5:c.1875G>T
• SIK1 p.Leu625Leu

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_173354.5(SIK1):​c.1875G>T​(p.Leu625Leu) 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: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.887
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-43417644-C-A is Benign according to our data. Variant chr21-43417644-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.887 with no splicing effect.

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.1875G>T	p.Leu625Leu	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.1875G>T	p.Leu625Leu	synonymous	Exon 13 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1728G>T	p.Leu576Leu	synonymous	Exon 12 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1593G>T	p.Leu531Leu	synonymous	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000142 AC: 3 AN: 210694 AF XY: 0.0000173

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: 0.0000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 337580 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 167270

African (AFR) AF: 0.00 AC: 0 AN: 14750

American (AMR) AF: 0.00 AC: 0 AN: 3368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6936

East Asian (EAS) AF: 0.00 AC: 0 AN: 7432

South Asian (SAS) AF: 0.00 AC: 0 AN: 21100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 261428

Other (OTH) AF: 0.00 AC: 0 AN: 15956

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs376554812;

hg19: chr21-44837524;