rs106287

chr6-31967973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006929.5(SKIC2):c.2749G>A(p.Val917Met) variant causes a missense change. The variant allele was found at a frequency of 0.0307 in 1,613,070 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (56 hom., cov: 32)
  • Exomes 𝑓: 0.032 (922 hom.)
• Consequence: SKIC2 NM_006929.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.38

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=0.0037950873).
• BP6: Variant 6-31967973-G-A is Benign according to our data. Variant chr6-31967973-G-A is described in ClinVar as [Benign]. Clinvar id is 356342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0207 (3149/152344) while in subpopulation AMR AF= 0.0376 (576/15308). AF 95% confidence interval is 0.0351. There are 56 homozygotes in gnomad4. There are 1403 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKIC2	NM_006929.5	c.2749G>A	p.Val917Met	missense_variant	23/28	ENST00000375394.7
SKIC2	XM_011514815.4	c.2749G>A	p.Val917Met	missense_variant	23/25
SKIC2	XM_047419259.1	c.2749G>A	p.Val917Met	missense_variant	23/25
SKIC2	XM_047419260.1	c.2749G>A	p.Val917Met	missense_variant	23/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKIC2	ENST00000375394.7	c.2749G>A	p.Val917Met	missense_variant	23/28	1	NM_006929.5	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3148 AN: 152226 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0184 AC: 4541 AN: 246340 Hom.: 83 AF XY: 0.0181 AC XY: 2434 AN XY: 134318

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0318 AC: 46450 AN: 1460726 Hom.: 922 Cov.: 35 AF XY: 0.0303 AC XY: 22010 AN XY: 726674

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00417

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0207 AC: 3149 AN: 152344 Hom.: 56 Cov.: 32 AF XY: 0.0188 AC XY: 1403 AN XY: 74500

Gnomad4 AFR AF: 0.00710

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.0313

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0261 Hom.: 116

Bravo AF: 0.0242

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0480 AC: 185

ESP6500AA AF: 0.00563 AC: 17

ESP6500EA AF: 0.0336 AC: 182

ExAC AF: 0.0163 AC: 1923

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0304

EpiControl AF: 0.0298

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	0.33
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.091
MPC		1.1
ClinPred		0.016	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.63

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: rs106287; hg19: chr6-31935750;