6-31968902-C-T

Variant names:

• chr6-31968902-C-T
• rs449643
• NM_006929.5:c.3212C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006929.5(SKIC2):​c.3212C>T​(p.Ala1071Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,372 control chromosomes in the GnomAD database, including 19,202 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1071A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3497 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15705 hom.)
• Consequence: SKIC2 NM_006929.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.53
• Publications: 47 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051842034).
• BP6: Variant 6-31968902-C-T is Benign according to our data. Variant chr6-31968902-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 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.3212C>T	p.Ala1071Val	missense	Exon 26 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.3212C>T	p.Ala1071Val	missense	Exon 26 of 28	ENSP00000364543.2	Q15477
	SKIC2	ENST00000465703.5	TSL:1	n.3848C>T		non_coding_transcript_exon	Exon 22 of 23
	SKIC2	ENST00000962078.1		c.3314C>T	p.Ala1105Val	missense	Exon 27 of 29	ENSP00000632137.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28640 AN: 152026 Hom.: 3490 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.0674

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.145 AC: 35689 AN: 246308 AF XY: 0.147

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0990

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.138 AC: 201749 AN: 1460228 Hom.: 15705 Cov.: 36 AF XY: 0.140 AC XY: 101366 AN XY: 726416

African (AFR) AF: 0.347 AC: 11614 AN: 33470

American (AMR) AF: 0.128 AC: 5719 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2678 AN: 26128

East Asian (EAS) AF: 0.0981 AC: 3895 AN: 39694

South Asian (SAS) AF: 0.223 AC: 19214 AN: 86244

European-Finnish (FIN) AF: 0.0743 AC: 3884 AN: 52258

Middle Eastern (MID) AF: 0.135 AC: 780 AN: 5766

European-Non Finnish (NFE) AF: 0.130 AC: 144659 AN: 1111582

Other (OTH) AF: 0.154 AC: 9306 AN: 60364

GnomAD4 genome AF: 0.189 AC: 28680 AN: 152144 Hom.: 3497 Cov.: 32 AF XY: 0.186 AC XY: 13834 AN XY: 74386

African (AFR) AF: 0.341 AC: 14144 AN: 41462

American (AMR) AF: 0.183 AC: 2801 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3466

East Asian (EAS) AF: 0.0983 AC: 509 AN: 5178

South Asian (SAS) AF: 0.202 AC: 972 AN: 4822

European-Finnish (FIN) AF: 0.0674 AC: 714 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8646 AN: 68004

Other (OTH) AF: 0.206 AC: 436 AN: 2112

Alfa AF: 0.141 Hom.: 7321

Bravo AF: 0.204

TwinsUK AF: 0.128 AC: 474

ALSPAC AF: 0.141 AC: 545

ESP6500AA AF: 0.314 AC: 947

ESP6500EA AF: 0.124 AC: 670

ExAC AF: 0.149 AC: 17562

Asia WGS AF: 0.223 AC: 777 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.130

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	0.088
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Sift4G	Benign	0.28	T
Polyphen		0.98	D
Vest4		0.052
MPC		0.38
ClinPred		0.010	T
GERP RS		1.7
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.045
gMVP		0.24
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs449643; hg19: chr6-31936679; COSMIC: COSV61714572; COSMIC: COSV61714572;