rs369897512

Positions:

• chr21-43419026-G-A
• chr21-43419026-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_173354.5(SIK1):​c.1457C>T​(p.Ala486Val) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.92

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06352651).
• BP6: Variant 21-43419026-G-A is Benign according to our data. Variant chr21-43419026-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574251.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1457C>T	p.Ala486Val	missense_variant	11/14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1310C>T	p.Ala437Val	missense_variant	10/13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1457C>T	p.Ala486Val	missense_variant	11/14	1	NM_173354.5	ENSP00000270162	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000283 AC: 37 AN: 130660 Hom.: 1 AF XY: 0.000244 AC XY: 17 AN XY: 69722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000299

Gnomad ASJ exome AF: 0.000281

Gnomad EAS exome AF: 0.0000968

Gnomad SAS exome AF: 0.000934

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00103

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000107 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000121 AC: 11

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.85	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.11
Sift	Benign	0.046	D
Sift4G	Benign	0.33	T
Polyphen		0.38	B
Vest4		0.21
MutPred		0.15		Loss of glycosylation at S482 (P = 0.2316);
MVP		0.19
MPC		0.17
ClinPred		0.079	T
GERP RS		3.7
Varity_R		0.079
gMVP		0.31

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: rs369897512; hg19: chr21-44838906; COSMIC: COSV54258777; COSMIC: COSV54258777;