rs144693254

Variant names:

• chr21-43418534-G-A
• rs144693254
• NM_173354.5:c.1470C>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.1470C>T​(p.Val490Val) 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.573
• 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)
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-43418534-G-A is Benign according to our data. Variant chr21-43418534-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.573 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1470C>T	p.Val490Val	synonymous_variant	Exon 12 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1323C>T	p.Val441Val	synonymous_variant	Exon 11 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1470C>T	p.Val490Val	synonymous_variant	Exon 12 of 14	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00466 AC: 1124 AN: 240954 AF XY: 0.00521

Gnomad AFR exome AF: 0.000704

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00524

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00574

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000321 AC: 1 AN: 3118 Hom.: 0 Cov.: 0 AF XY: 0.000593 AC XY: 1 AN XY: 1686

African (AFR) AF: 0.00 AC: 0 AN: 134

American (AMR) AF: 0.00 AC: 0 AN: 452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 62

East Asian (EAS) AF: 0.00 AC: 0 AN: 72

South Asian (SAS) AF: 0.00167 AC: 1 AN: 600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1598

Other (OTH) AF: 0.00 AC: 0 AN: 152

GnomAD4 genome Cov.: 0

Alfa AF: 0.00483 Hom.: 2

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIK1: BP4, BP7 -

Inborn genetic diseases Benign:1

May 03, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 30 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.81
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144693254; hg19: chr21-44838414;