rs34987632

Variant names:

• chr21-43419383-C-T
• rs34987632
• NM_173354.5:c.1215G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_173354.5(SIK1):​c.1215G>A​(p.Met405Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.95
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005063802).
• BP6: Variant 21-43419383-C-T is Benign according to our data. Variant chr21-43419383-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1215G>A	p.Met405Ile	missense	Exon 10 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.1215G>A	p.Met405Ile	missense	Exon 10 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1068G>A	p.Met356Ile	missense	Exon 9 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1215G>A	p.Met405Ile	missense	Exon 10 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00384 AC: 956 AN: 249070 AF XY: 0.00390

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00702

Gnomad OTH exome AF: 0.00346

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00609 Hom.: 4

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00388 AC: 470

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 30 (3)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.051
Sift	Benign	0.38	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.36		Loss of disorder (P = 0.0364)
MVP		0.29
MPC		0.15
ClinPred		0.0049	T
GERP RS		4.3
Varity_R		0.070
gMVP		0.37
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34987632; hg19: chr21-44839263;