rs437179

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006929.5(SKIC2):c.640A>C(p.Met214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,613,104 control chromosomes in the GnomAD database, including 424,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 47013 hom., cov: 32)

Exomes 𝑓: 0.71 ( 377735 hom. )

Consequence

SKIC2
NM_006929.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0210

Publications

71 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.570951E-7).

BP6

Variant 6-31961237-A-C is Benign according to our data. Variant chr6-31961237-A-C is described in ClinVar as Benign. ClinVar VariationId is 356318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC2	NM_006929.5 link	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 28	ENST00000375394.7	NP_008860.4	Q15477A0A1U9X8J1
SKIC2	XM_011514815.4 link	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 25		XP_011513117.1	A0A8V8TLC0
SKIC2	XM_047419259.1 link	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 25		XP_047275215.1
SKIC2	XM_047419260.1 link	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 24		XP_047275216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7 link	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 28	1	NM_006929.5	ENSP00000364543.2		Q15477

Frequencies

GnomAD3 genomes

AF:

0.780

AC:

118616

AN:

152038

Hom.:

46957

Cov.:

show subpopulations

Gnomad AFR

AF:

0.906

Gnomad AMI

AF:

0.848

Gnomad AMR

AF:

0.747

Gnomad ASJ

AF:

0.872

Gnomad EAS

AF:

0.680

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.741

Gnomad MID

AF:

0.902

Gnomad NFE

AF:

0.710

Gnomad OTH

AF:

0.818

GnomAD2 exomes

AF:

0.763

AC:

191158

AN:

250578

AF XY:

0.772

show subpopulations

Gnomad AFR exome

AF:

0.913

Gnomad AMR exome

AF:

0.729

Gnomad ASJ exome

AF:

0.872

Gnomad EAS exome

AF:

0.705

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.720

Gnomad OTH exome

AF:

0.764

GnomAD4 exome

AF:

0.714

AC:

1043709

AN:

1460948

Hom.:

377735

Cov.:

AF XY:

0.722

AC XY:

524472

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.911

AC:

30427

AN:

33384

American (AMR)

AF:

0.736

AC:

32716

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.867

AC:

22604

AN:

26084

East Asian (EAS)

AF:

0.661

AC:

26254

AN:

39692

South Asian (SAS)

AF:

0.895

AC:

77148

AN:

86170

European-Finnish (FIN)

AF:

0.725

AC:

38726

AN:

53404

Middle Eastern (MID)

AF:

0.894

AC:

5153

AN:

5766

European-Non Finnish (NFE)

AF:

0.689

AC:

766229

AN:

1111666

Other (OTH)

AF:

0.737

AC:

44452

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

15625

31250

46875

62500

78125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19494

38988

58482

77976

97470

<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:

0.780

AC:

118732

AN:

152156

Hom.:

47013

Cov.:

AF XY:

0.783

AC XY:

58234

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.906

AC:

37604

AN:

41504

American (AMR)

AF:

0.747

AC:

11420

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

3023

AN:

3468

East Asian (EAS)

AF:

0.681

AC:

3510

AN:

5156

South Asian (SAS)

AF:

0.887

AC:

4276

AN:

4822

European-Finnish (FIN)

AF:

0.741

AC:

7849

AN:

10598

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.710

AC:

48281

AN:

67994

Other (OTH)

AF:

0.820

AC:

1733

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1334

2669

4003

5338

6672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.744

Hom.:

135730

Bravo

AF:

0.787

TwinsUK

AF:

0.678

AC:

2513

ALSPAC

AF:

0.686

AC:

2642

ESP6500AA

AF:

0.897

AC:

3950

ESP6500EA

AF:

0.711

AC:

6116

ExAC

AF:

0.769

AC:

93412

Asia WGS

AF:

0.844

AC:

2933

AN:

3478

EpiCase

AF:

0.744

EpiControl

AF:

0.762

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 03, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Trichohepatoenteric syndrome 2

Benign:2

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28173125) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.9

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.012

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.0033

MetaRNN

Benign

5.6e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.0

PhyloP100

-0.021

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.51

REVEL

Benign

0.022

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.033

MutPred

0.25

Gain of catalytic residue at M214 (P = 0.0565);

MPC

0.36

ClinPred

0.00034

GERP RS

2.3

Varity_R

0.084

gMVP

0.16

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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