rs768404256

Variant names:

• chr21-43416852-G-A
• rs768404256
• NM_173354.5:c.2242C>T

Variant summary

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

The NM_173354.5(SIK1):​c.2242C>T​(p.Arg748Cys) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R748H) 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.36
• Publications: 0 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=0.061491936).

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.2242C>T	p.Arg748Cys	missense	Exon 14 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.2242C>T	p.Arg748Cys	missense	Exon 14 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.2095C>T	p.Arg699Cys	missense	Exon 13 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1960C>T	p.Arg654Cys	missense	Exon 13 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000216 AC: 5 AN: 231844 AF XY: 0.0000314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000290

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 40668 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20682

African (AFR) AF: 0.00 AC: 0 AN: 2570

American (AMR) AF: 0.00 AC: 0 AN: 876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2070

East Asian (EAS) AF: 0.00 AC: 0 AN: 3802

South Asian (SAS) AF: 0.00 AC: 0 AN: 1374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 25350

Other (OTH) AF: 0.00 AC: 0 AN: 3128

GnomAD4 genome Cov.: 0

ExAC AF: 0.0000497 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.16
Sift	Benign	0.26	T
Sift4G	Benign	0.061	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.28		Gain of catalytic residue at L749 (P = 0.0174)
MVP		0.10
MPC		0.19
ClinPred		0.073	T
GERP RS		-2.2
Varity_R		0.041
gMVP		0.38
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs768404256; hg19: chr21-44836732; COSMIC: COSV99532628; COSMIC: COSV99532628;