rs786205163

Positions:

• chr21-43417613-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_173354.5(SIK1):​c.1906G>A​(p.Gly636Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 1)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.899

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 21-43417613-C-T is Pathogenic according to our data. Variant chr21-43417613-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190109.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.088878006). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1906G>A	p.Gly636Ser	missense_variant	13/14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1759G>A	p.Gly587Ser	missense_variant	12/13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1906G>A	p.Gly636Ser	missense_variant	13/14	1	NM_173354.5	ENSP00000270162	P1

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 281374 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 138464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.084
Sift	Benign	0.25	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.12
MutPred		0.17		Gain of glycosylation at G636 (P = 0.0042);
MVP		0.44
MPC		0.16
ClinPred		0.073	T
GERP RS		-0.48
Varity_R		0.038
gMVP		0.17

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: rs786205163; hg19: chr21-44837493;