21-43419113-T-G

Variant names:

• chr21-43419113-T-G
• rs377535420
• NM_173354.5:c.1370A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_173354.5(SIK1):​c.1370A>C​(p.Glu457Ala) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E457E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.27
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34683815).
• BP6: Variant 21-43419113-T-G is Benign according to our data. Variant chr21-43419113-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 571730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1370A>C	p.Glu457Ala	missense_variant	Exon 11 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1223A>C	p.Glu408Ala	missense_variant	Exon 10 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1370A>C	p.Glu457Ala	missense_variant	Exon 11 of 14	1	NM_173354.5	ENSP00000270162.6
SIK1	ENST00000644871.1	n.*181A>C		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000652 AC: 10 AN: 153446 AF XY: 0.0000610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000155 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000439 AC: 5

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Oct 13, 2023

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

Oct 14, 2024

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
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.048	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.43
MVP		0.31
MPC		0.27
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.44
gMVP		0.39
Mutation Taster		=89/11	polymorphism

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: rs377535420; hg19: chr21-44838993;