21-43416758-A-T

Position:

• chr21-43416758-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_173354.5(SIK1):​c.2336T>A​(p.Phe779Tyr) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34350574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIK1	NM_173354.5	c.2336T>A	p.Phe779Tyr	missense_variant	14/14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.2189T>A	p.Phe730Tyr	missense_variant	13/13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.2336T>A	p.Phe779Tyr	missense_variant	14/14	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The missense variant c.2336T>A (p.Phe779Tyr) in the SIK1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Phe at position 779 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen, SIFT and MutationTaster) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Phe779Tyr in SIK1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.024	B
Vest4		0.56
MutPred		0.57		Loss of stability (P = 0.0978);
MVP		0.44
MPC		0.62
ClinPred		0.82	D
GERP RS		2.6
Varity_R		0.36
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-44836638;