21-43417080-C-T

Variant names:

• chr21-43417080-C-T
• rs751934560
• NM_173354.5:c.2014G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_173354.5(SIK1):​c.2014G>A​(p.Gly672Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G672R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0310
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043696582).
• BP6: Variant 21-43417080-C-T is Benign according to our data. Variant chr21-43417080-C-T is described in ClinVar as Benign. ClinVar VariationId is 476096.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.2014G>A	p.Gly672Ser	missense	Exon 14 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.2014G>A	p.Gly672Ser	missense	Exon 14 of 14	ENSP00000270162.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 9366 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

GnomAD2 exomes AF: 0.0000123 AC: 1 AN: 81624 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000806

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 9380 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4338

African (AFR) AF: 0.00 AC: 0 AN: 4130

American (AMR) AF: 0.00 AC: 0 AN: 442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 306

East Asian (EAS) AF: 0.00 AC: 0 AN: 162

South Asian (SAS) AF: 0.00 AC: 0 AN: 194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 86

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 12

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 3900

Other (OTH) AF: 0.00 AC: 0 AN: 84

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000931 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.81
DANN	Benign	0.71
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.031
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.11
Sift	Benign	0.53	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.15		Gain of glycosylation at G672 (P = 0.0045)
MVP		0.30
MPC		0.14
ClinPred		0.030	T
GERP RS		-6.0
Varity_R		0.022
gMVP		0.059
Mutation Taster		=98/2	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: rs751934560; hg19: chr21-44836960;