rs438999

Variant names:

• chr6-31960529-A-G
• rs438999
• NM_006929.5:c.452A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-31960529-A-G
• chr6-31960529-A-C
• chr6-31960529-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_006929.5(SKIC2):​c.452A>G​(p.Gln151Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0997 in 1,611,646 control chromosomes in the GnomAD database, including 8,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1234 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7746 hom.)
• Consequence: SKIC2 NM_006929.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.65
• Publications: 56 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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• trichohepatoenteric syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-31960529-A-G is Benign according to our data. Variant chr6-31960529-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006929.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIC2	NM_006929.5	MANE Select	c.452A>G	p.Gln151Arg	missense	Exon 5 of 28	NP_008860.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKIC2	ENST00000375394.7	TSL:1 MANE Select	c.452A>G	p.Gln151Arg	missense	Exon 5 of 28	ENSP00000364543.2	Q15477
	SKIC2	ENST00000465703.5	TSL:1	n.504A>G		non_coding_transcript_exon	Exon 5 of 23
	SKIC2	ENST00000962078.1		c.452A>G	p.Gln151Arg	missense	Exon 5 of 29	ENSP00000632137.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17857 AN: 151898 Hom.: 1235 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0911

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.0970 AC: 24386 AN: 251370 AF XY: 0.0994

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0708

Gnomad ASJ exome AF: 0.0520

Gnomad EAS exome AF: 0.0619

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0978 AC: 142765 AN: 1459630 Hom.: 7746 Cov.: 30 AF XY: 0.0986 AC XY: 71647 AN XY: 726286

African (AFR) AF: 0.190 AC: 6350 AN: 33420

American (AMR) AF: 0.0742 AC: 3318 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 1445 AN: 26116

East Asian (EAS) AF: 0.0737 AC: 2924 AN: 39694

South Asian (SAS) AF: 0.149 AC: 12834 AN: 86210

European-Finnish (FIN) AF: 0.0651 AC: 3478 AN: 53420

Middle Eastern (MID) AF: 0.0691 AC: 398 AN: 5762

European-Non Finnish (NFE) AF: 0.0950 AC: 105458 AN: 1109974

Other (OTH) AF: 0.109 AC: 6560 AN: 60312

GnomAD4 genome AF: 0.118 AC: 17879 AN: 152016 Hom.: 1234 Cov.: 32 AF XY: 0.115 AC XY: 8583 AN XY: 74318

African (AFR) AF: 0.194 AC: 8019 AN: 41438

American (AMR) AF: 0.102 AC: 1551 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3470

East Asian (EAS) AF: 0.0624 AC: 322 AN: 5164

South Asian (SAS) AF: 0.134 AC: 642 AN: 4806

European-Finnish (FIN) AF: 0.0577 AC: 611 AN: 10586

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0911 AC: 6191 AN: 67982

Other (OTH) AF: 0.130 AC: 274 AN: 2104

Alfa AF: 0.0944 Hom.: 3652

Bravo AF: 0.125

TwinsUK AF: 0.0949 AC: 352

ALSPAC AF: 0.104 AC: 402

ESP6500AA AF: 0.184 AC: 809

ESP6500EA AF: 0.0880 AC: 757

ExAC AF: 0.0997 AC: 12107

Asia WGS AF: 0.156 AC: 539 AN: 3478

EpiCase AF: 0.0870

EpiControl AF: 0.0885

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Trichohepatoenteric syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.047
Sift	Benign	0.068	T
Sift4G	Benign	0.12	T
Polyphen		0.039	B
Vest4		0.098
MPC		0.43
ClinPred		0.038	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.62
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: 0

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

Other links and lift over

dbSNP: rs438999; hg19: chr6-31928306; COSMIC: COSV64812335; COSMIC: COSV64812335;