rs145582574

Variant names:

• chr21-43419906-G-C
• rs145582574
• NM_173354.5:c.1072C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-43419906-G-C
• chr21-43419906-G-T

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.1072C>G​(p.Pro358Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 0)
  • Exomes 𝑓: 0.022 (488 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.64
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043595433).
• BP6: Variant 21-43419906-G-C is Benign according to our data. Variant chr21-43419906-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476075.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.1072C>G	p.Pro358Ala	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.1072C>G	p.Pro358Ala	missense	Exon 9 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880889.1		c.1072C>G	p.Pro358Ala	missense	Exon 9 of 13	ENSP00000550948.1
	SIK1	ENST00000880890.1		c.972+328C>G		intron	N/A	ENSP00000550949.1

Frequencies

GnomAD3 genomes AF: 0.00957 AC: 45 AN: 4704 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.000867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00794

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0208

GnomAD2 exomes AF: 0.00244 AC: 558 AN: 228454 AF XY: 0.00235

Gnomad AFR exome AF: 0.000436

Gnomad AMR exome AF: 0.000367

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00248

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0219 AC: 1178 AN: 53800 Hom.: 488 Cov.: 0 AF XY: 0.0224 AC XY: 630 AN XY: 28152

African (AFR) AF: 0.00532 AC: 7 AN: 1316

American (AMR) AF: 0.00890 AC: 5 AN: 562

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 25 AN: 1780

East Asian (EAS) AF: 0.00 AC: 0 AN: 3686

South Asian (SAS) AF: 0.00279 AC: 11 AN: 3940

European-Finnish (FIN) AF: 0.122 AC: 162 AN: 1332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.0243 AC: 921 AN: 37906

Other (OTH) AF: 0.0156 AC: 47 AN: 3016

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00956 AC: 45 AN: 4706 Hom.: 14 Cov.: 0 AF XY: 0.0112 AC XY: 23 AN XY: 2060

African (AFR) AF: 0.000865 AC: 1 AN: 1156

American (AMR) AF: 0.00 AC: 0 AN: 260

Ashkenazi Jewish (ASJ) AF: 0.00794 AC: 2 AN: 252

East Asian (EAS) AF: 0.00 AC: 0 AN: 96

South Asian (SAS) AF: 0.00 AC: 0 AN: 112

European-Finnish (FIN) AF: 0.0517 AC: 3 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.0141 AC: 38 AN: 2686

Other (OTH) AF: 0.0208 AC: 1 AN: 48

Alfa AF: 0.00287 Hom.: 8

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000913 AC: 4

ESP6500EA AF: 0.00350 AC: 30

ExAC AF: 0.00301 AC: 363

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.076
Sift	Benign	0.26	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.32
MPC		0.18
ClinPred		0.0063	T
GERP RS		3.0
Varity_R		0.035
gMVP		0.15
Mutation Taster		=97/3	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: rs145582574; hg19: chr21-44839786; COSMIC: COSV54258051; COSMIC: COSV54258051;