rs36038685

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_006929.5(SKIC2):c.970C>T(p.Arg324Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,612,886 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 12 hom., cov: 32)

Exomes 𝑓: 0.012 ( 183 hom. )

Consequence

SKIC2
NM_006929.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.506

Publications

12 publications found

Variant links:

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

SKIC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 6-31961960-C-T is Benign according to our data. Variant chr6-31961960-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1807/152322) while in subpopulation AFR AF = 0.0174 (725/41574). AF 95% confidence interval is 0.0164. There are 12 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC2	NM_006929.5 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 10 of 28	ENST00000375394.7	NP_008860.4	Q15477A0A1U9X8J1
SKIC2	XM_011514815.4 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 10 of 25		XP_011513117.1	A0A8V8TLC0
SKIC2	XM_047419259.1 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 10 of 25		XP_047275215.1
SKIC2	XM_047419260.1 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 10 of 24		XP_047275216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 10 of 28	1	NM_006929.5	ENSP00000364543.2		Q15477

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1804

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00807

AC:

1990

AN:

246674

AF XY:

0.00807

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.00722

Gnomad ASJ exome

AF:

0.0238

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00856

GnomAD4 exome

AF:

0.0124

AC:

18172

AN:

1460564

Hom.:

183

Cov.:

AF XY:

0.0121

AC XY:

8772

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.0183

AC:

611

AN:

33474

American (AMR)

AF:

0.00778

AC:

348

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

608

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00189

AC:

163

AN:

86256

European-Finnish (FIN)

AF:

0.000650

AC:

AN:

52308

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0138

AC:

15356

AN:

1111824

Other (OTH)

AF:

0.0163

AC:

982

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

881

1761

2642

3522

4403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0119

AC:

1807

AN:

152322

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

800

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0174

AC:

725

AN:

41574

American (AMR)

AF:

0.00771

AC:

118

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5192

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

836

AN:

68020

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.0165

AC:

ESP6500EA

AF:

0.0126

AC:

ExAC

AF:

0.00796

AC:

944

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SKIC2: BP4, BS1, BS2 -

Aug 31, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Trichohepatoenteric syndrome 2

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.12

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.5

PhyloP100

0.51

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0080

Polyphen

0.96

Vest4

0.39

MVP

0.92

MPC

0.86

ClinPred

0.092

GERP RS

4.8

Varity_R

0.36

gMVP

0.55

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over