6-31962574-A-G

Variant names:

• chr6-31962574-A-G
• rs2734331
• NM_006929.5:c.1200A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006929.5(SKIC2):​c.1200A>G​(p.Thr400Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,018 control chromosomes in the GnomAD database, including 1,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (172 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1353 hom.)
• Consequence: SKIC2 NM_006929.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-31962574-A-G is Benign according to our data. Variant chr6-31962574-A-G is described in ClinVar as Benign. ClinVar VariationId is 356326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 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.1200A>G	p.Thr400Thr	synonymous	Exon 11 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.1200A>G	p.Thr400Thr	synonymous	Exon 11 of 28	ENSP00000364543.2
	SKIC2	ENST00000465703.5	TSL:1	n.1513A>G		non_coding_transcript_exon	Exon 9 of 23
	SKIC2	ENST00000962078.1		c.1200A>G	p.Thr400Thr	synonymous	Exon 11 of 29	ENSP00000632137.1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5695 AN: 152114 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0501

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0473 AC: 11844 AN: 250258 AF XY: 0.0460

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0351

Gnomad NFE exome AF: 0.0398

Gnomad OTH exome AF: 0.0541

GnomAD4 exome AF: 0.0365 AC: 53314 AN: 1460786 Hom.: 1353 Cov.: 34 AF XY: 0.0364 AC XY: 26479 AN XY: 726652

African (AFR) AF: 0.0148 AC: 495 AN: 33468

American (AMR) AF: 0.0507 AC: 2266 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2642 AN: 26014

East Asian (EAS) AF: 0.0834 AC: 3310 AN: 39694

South Asian (SAS) AF: 0.0354 AC: 3051 AN: 86172

European-Finnish (FIN) AF: 0.0350 AC: 1869 AN: 53364

Middle Eastern (MID) AF: 0.0569 AC: 328 AN: 5764

European-Non Finnish (NFE) AF: 0.0329 AC: 36584 AN: 1111284

Other (OTH) AF: 0.0459 AC: 2769 AN: 60338

GnomAD4 genome AF: 0.0374 AC: 5692 AN: 152232 Hom.: 172 Cov.: 32 AF XY: 0.0378 AC XY: 2812 AN XY: 74448

African (AFR) AF: 0.0150 AC: 625 AN: 41538

American (AMR) AF: 0.0501 AC: 766 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3464

East Asian (EAS) AF: 0.110 AC: 571 AN: 5174

South Asian (SAS) AF: 0.0530 AC: 256 AN: 4826

European-Finnish (FIN) AF: 0.0365 AC: 387 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2574 AN: 68006

Other (OTH) AF: 0.0501 AC: 106 AN: 2116

Alfa AF: 0.0407 Hom.: 728

Bravo AF: 0.0391

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0351

EpiControl AF: 0.0399

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.81
DANN	Benign	0.62
PhyloP100		-1.6
Mutation Taster		=93/7	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: rs2734331; hg19: chr6-31930351; COSMIC: COSV64811643; COSMIC: COSV64811643;