21-43417593-G-C

Variant names:

• chr21-43417593-G-C
• NM_173354.5:c.1926C>G
• SIK1 p.Ala642Ala

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_173354.5(SIK1):​c.1926C>G​(p.Ala642Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A642A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 1)
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-1.22 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.1926C>G	p.Ala642Ala	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.1926C>G	p.Ala642Ala	synonymous	Exon 13 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1779C>G	p.Ala593Ala	synonymous	Exon 12 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1644C>G	p.Ala548Ala	synonymous	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.33
PhyloP100		-1.2

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

hg19: chr21-44837473;