rs375664122

Variant names:

• chr21-43418546-G-A
• rs375664122
• NM_173354.5:c.1463-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43418546-G-A
• chr21-43418546-G-C
• chr21-43418546-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_173354.5(SIK1):​c.1463-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001562
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.256

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-43418546-G-A is Benign according to our data. Variant chr21-43418546-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476083.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1463-5C>T		splice_region_variant, intron_variant	Intron 11 of 13	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1316-5C>T		splice_region_variant, intron_variant	Intron 10 of 12		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1463-5C>T		splice_region_variant, intron_variant	Intron 11 of 13	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000750 AC: 18 AN: 239872 Hom.: 0 AF XY: 0.0000687 AC XY: 9 AN XY: 130974

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000516 AC: 1 AN: 1938 Hom.: 0 Cov.: 0 AF XY: 0.000949 AC XY: 1 AN XY: 1054

Gnomad4 AFR exome AF: 0.0179

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SIK1 c.1463-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.5e-05 in 239872 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SIK1 causing Developmental And Epileptic Encephalopathy, 30, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1463-5C>T in individuals affected with Developmental And Epileptic Encephalopathy, 30 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 476083). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Benign:1

Apr 11, 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 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs375664122; hg19: chr21-44838426;