rs3746951

Positions:

• chr21-43426136-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

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 (★★).

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

SIK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIK1	NM_173354.5	c.43G>A	p.Gly15Ser	missense_variant	2/14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.43G>A	p.Gly15Ser	missense_variant	2/13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.43G>A	p.Gly15Ser	missense_variant	2/14	1	NM_173354.5	ENSP00000270162.6
SIK1	ENST00000644750.1	c.43G>A	p.Gly15Ser	missense_variant	2/5			ENSP00000495479.1
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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 49. Only high quality variants are reported. -

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. -

Developmental and epileptic encephalopathy, 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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;.
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;