rs140222760

chr21-43418533-C-Gchr21-43418533-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173354.5(SIK1):c.1471G>C(p.Val491Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V491I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0810

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024900466).
• BP6: Variant 21-43418533-C-G is Benign according to our data. Variant chr21-43418533-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 476086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43418533-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.1471G>C	p.Val491Leu	missense_variant	12/14	ENST00000270162.8
SIK1	XM_011529474.3	c.1324G>C	p.Val442Leu	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.1471G>C	p.Val491Leu	missense_variant	12/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000340 AC: 82 AN: 241162 Hom.: 0 AF XY: 0.000358 AC XY: 47 AN XY: 131434

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000785

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: 0.000428

Gnomad OTH exome AF: 0.00118

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2988 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.000341 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000298 AC: 36

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 13, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2018

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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

SIK1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	4.8
Dann	Benign	0.92
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.11
Sift	Benign	0.077	T
Sift4G	Benign	0.63	T
Polyphen		0.014	B
Vest4		0.12
MVP		0.16
MPC		0.16
ClinPred		0.0072	T
GERP RS		-2.1
Varity_R		0.045
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140222760; hg19: chr21-44838413;