rs780535115

Variant names:

• chr21-43419884-C-T
• rs780535115
• NM_173354.5:c.1094G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_173354.5(SIK1):​c.1094G>A​(p.Arg365Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R365W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.08
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25556844).
• BP6: Variant 21-43419884-C-T is Benign according to our data. Variant chr21-43419884-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 566342.

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.1094G>A	p.Arg365Gln	missense	Exon 9 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.1094G>A	p.Arg365Gln	missense	Exon 9 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880889.1		c.1094G>A	p.Arg365Gln	missense	Exon 9 of 13	ENSP00000550948.1
	SIK1	ENST00000880890.1		c.972+350G>A		intron	N/A	ENSP00000550949.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000405 AC: 9 AN: 222078 AF XY: 0.0000415

Gnomad AFR exome AF: 0.0000734

Gnomad AMR exome AF: 0.000155

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 80528 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42000

African (AFR) AF: 0.00 AC: 0 AN: 1962

American (AMR) AF: 0.00 AC: 0 AN: 1040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 4636

South Asian (SAS) AF: 0.00 AC: 0 AN: 7032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 362

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56622

Other (OTH) AF: 0.00 AC: 0 AN: 4408

GnomAD4 genome Cov.: 0

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	0.094
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.010	D
Sift4G	Benign	0.56	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.15		Loss of glycosylation at P364 (P = 0.0497)
MVP		0.59
MPC		0.39
ClinPred		0.40	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.38
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs780535115; hg19: chr21-44839764; COSMIC: COSV54261530; COSMIC: COSV54261530;