rs773946657

Variant names:

• chr21-43417691-G-A
• rs773946657
• NM_173354.5:c.1828C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_173354.5(SIK1):​c.1828C>T​(p.Arg610Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic 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. R610H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000047 (1 hom., cov: 2)
  • Exomes 𝑓: 0.0000030 (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: 3.29
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000466 (2/42912) while in subpopulation NFE AF = 0.000125 (2/16008). AF 95% confidence interval is 0.0000216. There are 1 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 2. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1828C>T	p.Arg610Cys	missense	Exon 13 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.1828C>T	p.Arg610Cys	missense	Exon 13 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1681C>T	p.Arg561Cys	missense	Exon 12 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1546C>T	p.Arg516Cys	missense	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes AF: 0.0000466 AC: 2 AN: 42912 Hom.: 1 Cov.: 2

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: 0.000125

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000923 AC: 2 AN: 216600 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000626

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000295 AC: 1 AN: 338748 Hom.: 0 Cov.: 0 AF XY: 0.00000596 AC XY: 1 AN XY: 167726

⚠️ 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: 15050

American (AMR) AF: 0.00 AC: 0 AN: 3930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7120

East Asian (EAS) AF: 0.00 AC: 0 AN: 7510

South Asian (SAS) AF: 0.00 AC: 0 AN: 21354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1284

European-Non Finnish (NFE) AF: 0.00000382 AC: 1 AN: 261564

Other (OTH) AF: 0.00 AC: 0 AN: 15968

⚠️ 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 AF: 0.0000466 AC: 2 AN: 42912 Hom.: 1 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 19954

African (AFR) AF: 0.00 AC: 0 AN: 19104

American (AMR) AF: 0.00 AC: 0 AN: 2596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1180

East Asian (EAS) AF: 0.00 AC: 0 AN: 886

South Asian (SAS) AF: 0.00 AC: 0 AN: 1332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.000125 AC: 2 AN: 16008

Other (OTH) AF: 0.00 AC: 0 AN: 568

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000166 AC: 2

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	0.25
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.42		Loss of MoRF binding (P = 0.0024)
MVP		0.27
MPC		0.39
ClinPred		0.84	D
GERP RS		3.9
Varity_R		0.47
gMVP		0.32
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs773946657; hg19: chr21-44837571; COSMIC: COSV54258700; COSMIC: COSV54258700;