rs34487963

chr21-43418450-C-Achr21-43418450-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_173354.5(SIK1):c.1554G>T(p.Ala518=) 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A518A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0021 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 21-43418450-C-A is Benign according to our data. Variant chr21-43418450-C-A is described in ClinVar as [Benign]. Clinvar id is 476089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43418450-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00213 (20/9402) while in subpopulation SAS AF= 0.00394 (3/762). AF 95% confidence interval is 0.00107. There are 2 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 7841 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK1	NM_173354.5	c.1554G>T	p.Ala518=	synonymous_variant	12/14	ENST00000270162.8
SIK1	XM_011529474.3	c.1407G>T	p.Ala469=	synonymous_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK1	ENST00000270162.8	c.1554G>T	p.Ala518=	synonymous_variant	12/14	1	NM_173354.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMR AF: 0.00

GnomAD3 exomes AF: 0.0322 AC: 7841 AN: 243272 Hom.: 322 AF XY: 0.0372 AC XY: 4931 AN XY: 132596

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.00980

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0637

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.00650

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.00213 AC: 20 AN: 9402 Hom.: 2 Cov.: 0 AF XY: 0.00224 AC XY: 11 AN XY: 4906

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.00272

Gnomad4 SAS exome AF: 0.00394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Alfa AF: 0.0134 Hom.: 5

Asia WGS AF: 0.0790 AC: 272 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

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. -

Developmental and epileptic encephalopathy, 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.053
Dann	Benign	0.54

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: rs34487963; hg19: chr21-44838330;