rs106287

Variant names:

• chr6-31967973-G-A
• rs106287
• NM_006929.5:c.2749G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-31967973-G-A
• chr6-31967973-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• trichohepatoenteric syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• trichohepatoenteric syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC2	NM_006929.5	c.2749G>A	p.Val917Met	missense_variant	Exon 23 of 28	ENST00000375394.7	NP_008860.4
SKIC2	XM_011514815.4	c.2749G>A	p.Val917Met	missense_variant	Exon 23 of 25		XP_011513117.1
SKIC2	XM_047419259.1	c.2749G>A	p.Val917Met	missense_variant	Exon 23 of 25		XP_047275215.1
SKIC2	XM_047419260.1	c.2749G>A	p.Val917Met	missense_variant	Exon 23 of 24		XP_047275216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7	c.2749G>A	p.Val917Met	missense_variant	Exon 23 of 28	1	NM_006929.5	ENSP00000364543.2

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

GnomAD2 exomes AF: 0.0184 AC: 4541 AN: 246340 AF XY: 0.0181

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 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

African (AFR) AF: 0.00517 AC: 173 AN: 33480

American (AMR) AF: 0.0269 AC: 1202 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 344 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00417 AC: 218 AN: 52304

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0386 AC: 42893 AN: 1111988

Other (OTH) AF: 0.0266 AC: 1607 AN: 60382

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

African (AFR) AF: 0.00710 AC: 295 AN: 41570

American (AMR) AF: 0.0376 AC: 576 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00263 AC: 28 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2131 AN: 68032

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0261 Hom.: 295

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		4.4
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
Mutation Taster		=99/1	polymorphism (auto)

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: rs106287; hg19: chr6-31935750;