NM_173354.5:c.1828C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS1

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: Likely_benign. The variant received -3 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.

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;