NM_173354.5:c.1848C>T

Variant names:

• chr21-43417671-G-A
• rs430552
• NM_173354.5:c.1848C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_173354.5(SIK1):​c.1848C>T​(p.Pro616Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.298
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-43417671-G-A is Benign according to our data. Variant chr21-43417671-G-A is described in ClinVar as Benign. ClinVar VariationId is 586586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.298 with no splicing effect.

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.1848C>T	p.Pro616Pro	synonymous	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.1848C>T	p.Pro616Pro	synonymous	Exon 13 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1701C>T	p.Pro567Pro	synonymous	Exon 12 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1566C>T	p.Pro522Pro	synonymous	Exon 12 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 42124 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: 0.800 AC: 173778 AN: 217226 AF XY: 0.796

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.901

Gnomad ASJ exome AF: 0.732

Gnomad EAS exome AF: 0.890

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.797

Gnomad OTH exome AF: 0.785

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 344962 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 171056

African (AFR) AF: 0.00 AC: 0 AN: 15500

American (AMR) AF: 0.00 AC: 0 AN: 4226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7454

East Asian (EAS) AF: 0.00 AC: 0 AN: 7586

South Asian (SAS) AF: 0.00 AC: 0 AN: 22120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1426

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 265088

Other (OTH) AF: 0.00 AC: 0 AN: 16342

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 42124 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 19668

African (AFR) AF: 0.00 AC: 0 AN: 18752

American (AMR) AF: 0.00 AC: 0 AN: 2546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1152

East Asian (EAS) AF: 0.00 AC: 0 AN: 880

South Asian (SAS) AF: 0.00 AC: 0 AN: 1328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 15688

Other (OTH) AF: 0.00 AC: 0 AN: 568

Alfa AF: 0.587 Hom.: 10699

Asia WGS AF: 0.766 AC: 2662 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Developmental and epileptic encephalopathy, 30 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs430552; hg19: chr21-44837551; COSMIC: COSV54258613; COSMIC: COSV54258613;