rs374476526

chr21-43420344-CGGG-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_173354.5(SIK1):c.859_861del(p.Pro287del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P287P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_173354.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 21-43420344-CGGG-C is Benign according to our data. Variant chr21-43420344-CGGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 542718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.859_861del	p.Pro287del	inframe_deletion	8/14	ENST00000270162.8
SIK1	XM_011529474.3	c.859_861del	p.Pro287del	inframe_deletion	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.859_861del	p.Pro287del	inframe_deletion	8/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000437 AC: 108 AN: 247306 Hom.: 0 AF XY: 0.000364 AC XY: 49 AN XY: 134440

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 0

Alfa AF: 0.000334 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2018

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

SIK1: BS1, BS2 -

Developmental and epileptic encephalopathy, 30 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs374476526; hg19: chr21-44840224;