rs112011493

Variant names:

• chr21-43420416-C-T
• rs112011493
• NM_173354.5:c.790G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_173354.5(SIK1):​c.790G>A​(p.Ala264Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.470
• Publications: 6 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)
• early myoclonic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008735865).
• BP6: Variant 21-43420416-C-T is Benign according to our data. Variant chr21-43420416-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.790G>A	p.Ala264Thr	missense_variant	Exon 8 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.790G>A	p.Ala264Thr	missense_variant	Exon 8 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.790G>A	p.Ala264Thr	missense_variant	Exon 8 of 14	1	NM_173354.5	ENSP00000270162.6
SIK1	ENST00000644689.1	n.*22G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00106 AC: 254 AN: 238536 AF XY: 0.00108

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0000560

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00238

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00146 Hom.: 1

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIK1: BS1, BS2 -

Inborn genetic diseases Benign:1

Nov 15, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 30 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
PhyloP100		0.47
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.016
Sift	Benign	0.30	T
Sift4G	Benign	0.68	T
Polyphen		0.024	B
Vest4		0.10
MVP		0.20
MPC		0.14
ClinPred		0.0026	T
GERP RS		-0.12
Varity_R		0.083
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs112011493; hg19: chr21-44840296;