rs3911893

Positions:

• chr6-31967790-G-A
• chr6-31967790-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006929.5(SKIC2):​c.2659G>A​(p.Asp887Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,612,958 control chromosomes in the GnomAD database, including 1,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (286 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1410 hom.)
• Consequence: SKIC2 NM_006929.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.420

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019786954).
• BP6: Variant 6-31967790-G-A is Benign according to our data. Variant chr6-31967790-G-A is described in ClinVar as [Benign]. Clinvar id is 356340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31967790-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIC2	NM_006929.5	c.2659G>A	p.Asp887Asn	missense_variant	22/28	ENST00000375394.7
SKIC2	XM_011514815.4	c.2659G>A	p.Asp887Asn	missense_variant	22/25
SKIC2	XM_047419259.1	c.2659G>A	p.Asp887Asn	missense_variant	22/25
SKIC2	XM_047419260.1	c.2659G>A	p.Asp887Asn	missense_variant	22/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIC2	ENST00000375394.7	c.2659G>A	p.Asp887Asn	missense_variant	22/28	1	NM_006929.5	P1

Frequencies

GnomAD3 genomes AF: 0.0553 AC: 8409 AN: 152162 Hom.: 287 Cov.: 32

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0659

GnomAD3 exomes AF: 0.0518 AC: 12769 AN: 246348 Hom.: 494 AF XY: 0.0489 AC XY: 6574 AN XY: 134320

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0357

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0398

Gnomad OTH exome AF: 0.0535

GnomAD4 exome AF: 0.0377 AC: 55109 AN: 1460678 Hom.: 1410 Cov.: 34 AF XY: 0.0374 AC XY: 27183 AN XY: 726664

Gnomad4 AFR exome AF: 0.0710

Gnomad4 AMR exome AF: 0.0570

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.0747

Gnomad4 SAS exome AF: 0.0370

Gnomad4 FIN exome AF: 0.0317

Gnomad4 NFE exome AF: 0.0328

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0553 AC: 8415 AN: 152280 Hom.: 286 Cov.: 32 AF XY: 0.0548 AC XY: 4081 AN XY: 74440

Gnomad4 AFR AF: 0.0766

Gnomad4 AMR AF: 0.0609

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.0556

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0417 Hom.: 318

Bravo AF: 0.0592

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0368 AC: 142

ESP6500AA AF: 0.0748 AC: 226

ESP6500EA AF: 0.0408 AC: 221

ExAC AF: 0.0507 AC: 5989

Asia WGS AF: 0.0660 AC: 228 AN: 3478

EpiCase AF: 0.0352

EpiControl AF: 0.0402

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Trichohepatoenteric syndrome 2 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.64	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.14	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.030
Sift	Benign	0.34	T
Sift4G	Benign	0.52	T
Polyphen		0.049	B
Vest4		0.037
MPC		0.37
ClinPred		0.0073	T
GERP RS		3.1
Varity_R		0.034
gMVP		0.39

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: rs3911893; hg19: chr6-31935567;