rs751294210

Variant names:

• chr21-43417602-G-A
• rs751294210
• NM_173354.5:c.1917C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_173354.5(SIK1):​c.1917C>T​(p.Gly639Gly) 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: 1)
  • Exomes 𝑓: 0.0000091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-43417602-G-A is Benign according to our data. Variant chr21-43417602-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 542721.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173354.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.1917C>T	p.Gly639Gly	synonymous	Exon 13 of 14	NP_775490.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1917C>T	p.Gly639Gly	synonymous	Exon 13 of 14	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD2 exomes AF: 0.0000451 AC: 6 AN: 132986 AF XY: 0.0000535

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000106

Gnomad FIN exome AF: 0.000123

Gnomad NFE exome AF: 0.0000153

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000908 AC: 2 AN: 220198 Hom.: 0 Cov.: 0 AF XY: 0.00000916 AC XY: 1 AN XY: 109124

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10208

American (AMR) AF: 0.00 AC: 0 AN: 1748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5060

East Asian (EAS) AF: 0.00 AC: 0 AN: 6278

South Asian (SAS) AF: 0.00 AC: 0 AN: 11914

European-Finnish (FIN) AF: 0.000241 AC: 1 AN: 4148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 852

European-Non Finnish (NFE) AF: 0.00000593 AC: 1 AN: 168706

Other (OTH) AF: 0.00 AC: 0 AN: 11284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 1

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.63
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs751294210; hg19: chr21-44837482; COSMIC: COSV99532364; COSMIC: COSV99532364;