rs3746951

chr21-43426136-C-T

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.43G>A(p.Gly15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 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. G15C) has been classified as Uncertain significance.

• 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: 1.03

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=0.0043837726).
• BP6: Variant 21-43426136-C-T is Benign according to our data. Variant chr21-43426136-C-T is described in ClinVar as [Benign]. Clinvar id is 586588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 51876 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.43G>A	p.Gly15Ser	missense_variant	2/14	ENST00000270162.8
SIK1	XM_011529474.3	c.43G>A	p.Gly15Ser	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.43G>A	p.Gly15Ser	missense_variant	2/14	1	NM_173354.5	P1
SIK1	ENST00000644750.1	c.43G>A	p.Gly15Ser	missense_variant	2/5
SIK1	ENST00000644276.1	n.140G>A		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.231 AC: 51876 AN: 224828 Hom.: 6444 AF XY: 0.227 AC XY: 27850 AN XY: 122434

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.243

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.219 Hom.: 2066

TwinsUK AF: 0.258 AC: 955

ALSPAC AF: 0.245 AC: 943

ESP6500AA AF: 0.0484 AC: 212

ESP6500EA AF: 0.258 AC: 2211

ExAC AF: 0.210 AC: 25220

Asia WGS AF: 0.162 AC: 567 AN: 3474

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

Jan 08, 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

Apr 20, 2017

- -

Developmental and epileptic encephalopathy, 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.51	N;.
REVEL	Benign	0.059
Sift	Benign	0.40	T;.
Sift4G	Benign	0.30	T;.
Polyphen		0.0070	B;.
Vest4		0.030
MPC		0.97
ClinPred		0.0047	T
GERP RS		2.4
Varity_R		0.069
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs3746951; hg19: chr21-44846016; COSMIC: COSV54259059; COSMIC: COSV54259059;