21-43418533-C-T

Variant names:

• chr21-43418533-C-T
• rs140222760
• NM_173354.5:c.1471G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173354.5(SIK1):​c.1471G>A​(p.Val491Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V491L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810
• Publications: 1 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: Orphanet, ClinGen, PanelApp Australia
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053058833).

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.1471G>A	p.Val491Ile	missense	Exon 12 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.1471G>A	p.Val491Ile	missense	Exon 12 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1324G>A	p.Val442Ile	missense	Exon 11 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1462+488G>A		intron	N/A	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000249 AC: 6 AN: 241162 AF XY: 0.0000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2988 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1608

African (AFR) AF: 0.00 AC: 0 AN: 126

American (AMR) AF: 0.00 AC: 0 AN: 422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 58

East Asian (EAS) AF: 0.00 AC: 0 AN: 74

South Asian (SAS) AF: 0.00 AC: 0 AN: 564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1548

Other (OTH) AF: 0.00 AC: 0 AN: 146

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000284 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.88
DANN	Benign	0.79
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-0.081
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.059
Sift	Benign	0.62	T
Sift4G	Benign	0.98	T
Polyphen		0.0070	B
Vest4		0.063
MutPred		0.18		Gain of catalytic residue at P493 (P = 0.0595)
MVP		0.10
MPC		0.11
ClinPred		0.013	T
GERP RS		-2.1
Varity_R		0.020
gMVP		0.086
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs140222760; hg19: chr21-44838413; COSMIC: COSV54258916; COSMIC: COSV54258916;