rs149713367

Positions:

• chr21-43419901-G-A
• chr21-43419901-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_173354.5(SIK1):​c.1077C>T​(p.Ala359=) 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)
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.50

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-43419901-G-A is Benign according to our data. Variant chr21-43419901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43419901-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.1077C>T	p.Ala359=	synonymous_variant	9/14	ENST00000270162.8
SIK1	XM_011529474.3	c.972+333C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.1077C>T	p.Ala359=	synonymous_variant	9/14	1	NM_173354.5	P1
SIK1	ENST00000644871.1	n.22C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000975 AC: 224 AN: 229800 Hom.: 1 AF XY: 0.00119 AC XY: 149 AN XY: 124924

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000573

Gnomad SAS exome AF: 0.00267

Gnomad FIN exome AF: 0.000156

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00211

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00108 Hom.: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2017

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

SIK1: BP4, BP7, BS2 -

Developmental and epileptic encephalopathy, 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	11
DANN	Benign	0.76

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: rs149713367; hg19: chr21-44839781;