rs2734331

Positions:

• chr6-31962574-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006929.5(SKIC2):​c.1200A>G​(p.Thr400Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,018 control chromosomes in the GnomAD database, including 1,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (172 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1353 hom.)
• Consequence: SKIC2 NM_006929.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57

Genes affected

SKIC2 (HGNC:10898): (SKI2 subunit of superkiller complex) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a human homologue of yeast SKI2 and may be involved in antiviral activity by blocking translation of poly(A) deficient mRNAs. This gene is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

SKIC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-31962574-A-G is Benign according to our data. Variant chr6-31962574-A-G is described in ClinVar as [Benign]. Clinvar id is 356326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31962574-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKIC2	NM_006929.5	c.1200A>G	p.Thr400Thr	synonymous_variant	11/28	ENST00000375394.7	NP_008860.4
SKIC2	XM_011514815.4	c.1200A>G	p.Thr400Thr	synonymous_variant	11/25		XP_011513117.1
SKIC2	XM_047419259.1	c.1200A>G	p.Thr400Thr	synonymous_variant	11/25		XP_047275215.1
SKIC2	XM_047419260.1	c.1200A>G	p.Thr400Thr	synonymous_variant	11/24		XP_047275216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7	c.1200A>G	p.Thr400Thr	synonymous_variant	11/28	1	NM_006929.5	ENSP00000364543.2

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5695 AN: 152114 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0501

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0473 AC: 11844 AN: 250258 Hom.: 445 AF XY: 0.0460 AC XY: 6225 AN XY: 135226

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.0345

Gnomad FIN exome AF: 0.0351

Gnomad NFE exome AF: 0.0398

Gnomad OTH exome AF: 0.0541

GnomAD4 exome AF: 0.0365 AC: 53314 AN: 1460786 Hom.: 1353 Cov.: 34 AF XY: 0.0364 AC XY: 26479 AN XY: 726652

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0834

Gnomad4 SAS exome AF: 0.0354

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0459

GnomAD4 genome AF: 0.0374 AC: 5692 AN: 152232 Hom.: 172 Cov.: 32 AF XY: 0.0378 AC XY: 2812 AN XY: 74448

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0414 Hom.: 355

Bravo AF: 0.0391

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0351

EpiControl AF: 0.0399

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Trichohepatoenteric syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.81
DANN	Benign	0.62

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: rs2734331; hg19: chr6-31930351; COSMIC: COSV64811643; COSMIC: COSV64811643;