21-43417675-G-C

Variant names:

• chr21-43417675-G-C
• rs430554
• NM_173354.5:c.1844C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173354.5(SIK1):​c.1844C>G​(p.Ala615Gly) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A615T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 25 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)
• early myoclonic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08974758).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.1844C>G	p.Ala615Gly	missense	Exon 13 of 14	NP_775490.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1844C>G	p.Ala615Gly	missense	Exon 13 of 14	ENSP00000270162.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 39028 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000300 AC: 1 AN: 333698 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 165184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14624

American (AMR) AF: 0.00 AC: 0 AN: 4154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7106

East Asian (EAS) AF: 0.00 AC: 0 AN: 7602

South Asian (SAS) AF: 0.00 AC: 0 AN: 20882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1366

European-Non Finnish (NFE) AF: 0.00000389 AC: 1 AN: 257348

Other (OTH) AF: 0.00 AC: 0 AN: 15728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 39028 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18162

African (AFR) AF: 0.00 AC: 0 AN: 16930

American (AMR) AF: 0.00 AC: 0 AN: 2426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1056

East Asian (EAS) AF: 0.00 AC: 0 AN: 884

South Asian (SAS) AF: 0.00 AC: 0 AN: 1228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 84

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14818

Other (OTH) AF: 0.00 AC: 0 AN: 536

Alfa AF: 0.00 Hom.: 75693

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.73
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.17
Sift	Uncertain	0.018	D
Sift4G	Benign	0.45	T
Polyphen		0.075	B
Vest4		0.17
MutPred		0.18		Gain of catalytic residue at A615 (P = 0.0207)
MVP		0.34
MPC		0.15
ClinPred		0.13	T
GERP RS		2.3
Varity_R		0.087
gMVP		0.080
Mutation Taster		=96/4	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: rs430554; hg19: chr21-44837555;