rs34164089

chr21-43419195-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173354.5(SIK1):c.1288C>T(p.Arg430Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R430Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.40

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037110746).
• BP6: Variant 21-43419195-G-A is Benign according to our data. Variant chr21-43419195-G-A is described in ClinVar as [Benign]. Clinvar id is 476080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.1288C>T	p.Arg430Trp	missense_variant	11/14	ENST00000270162.8
SIK1	XM_011529474.3	c.1141C>T	p.Arg381Trp	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.1288C>T	p.Arg430Trp	missense_variant	11/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00132 AC: 300 AN: 226782 Hom.: 1 AF XY: 0.00101 AC XY: 125 AN XY: 123550

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad SAS exome AF: 0.0000699

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000392

Gnomad OTH exome AF: 0.00195

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000791 Hom.: 0

ESP6500AA AF: 0.0153 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00150 AC: 181

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 18, 2018

- -

Developmental and epileptic encephalopathy, 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Benign	0.083	T
Polyphen		0.010	B
Vest4		0.20
MVP		0.13
MPC		0.45
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34164089; hg19: chr21-44839075;