6-31968891-T-C

Variant names:

• chr6-31968891-T-C
• rs410851
• NM_006929.5:c.3201T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006929.5(SKIC2):​c.3201T>C​(p.Tyr1067Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,612,252 control chromosomes in the GnomAD database, including 434,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48995 hom., cov: 32)
  • Exomes 𝑓: 0.72 (385106 hom.)
• Consequence: SKIC2 NM_006929.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.97
• Publications: 37 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.085).
• BP6: Variant 6-31968891-T-C is Benign according to our data. Variant chr6-31968891-T-C is described in ClinVar as Benign. ClinVar VariationId is 356345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC2	NM_006929.5	c.3201T>C	p.Tyr1067Tyr	synonymous_variant	Exon 26 of 28	ENST00000375394.7	NP_008860.4
SKIC2	XM_011514815.4	c.*223T>C		downstream_gene_variant			XP_011513117.1
SKIC2	XM_047419259.1	c.*242T>C		downstream_gene_variant			XP_047275215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7	c.3201T>C	p.Tyr1067Tyr	synonymous_variant	Exon 26 of 28	1	NM_006929.5	ENSP00000364543.2

Frequencies

GnomAD3 genomes AF: 0.796 AC: 121010 AN: 152034 Hom.: 48928 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.832

GnomAD2 exomes AF: 0.781 AC: 192300 AN: 246250 AF XY: 0.785

Gnomad AFR exome AF: 0.928

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.740

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.721 AC: 1053079 AN: 1460100 Hom.: 385106 Cov.: 60 AF XY: 0.728 AC XY: 528442 AN XY: 726350

African (AFR) AF: 0.927 AC: 31016 AN: 33474

American (AMR) AF: 0.853 AC: 38126 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 22691 AN: 26128

East Asian (EAS) AF: 0.689 AC: 27350 AN: 39680

South Asian (SAS) AF: 0.897 AC: 77412 AN: 86254

European-Finnish (FIN) AF: 0.732 AC: 38233 AN: 52234

Middle Eastern (MID) AF: 0.894 AC: 5154 AN: 5768

European-Non Finnish (NFE) AF: 0.691 AC: 768244 AN: 1111476

Other (OTH) AF: 0.743 AC: 44853 AN: 60368

GnomAD4 genome AF: 0.796 AC: 121137 AN: 152152 Hom.: 48995 Cov.: 32 AF XY: 0.801 AC XY: 59549 AN XY: 74378

African (AFR) AF: 0.920 AC: 38221 AN: 41528

American (AMR) AF: 0.848 AC: 12975 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 3032 AN: 3472

East Asian (EAS) AF: 0.684 AC: 3528 AN: 5156

South Asian (SAS) AF: 0.889 AC: 4290 AN: 4826

European-Finnish (FIN) AF: 0.748 AC: 7912 AN: 10572

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48387 AN: 67988

Other (OTH) AF: 0.834 AC: 1756 AN: 2106

Alfa AF: 0.743 Hom.: 94570

Bravo AF: 0.808

Asia WGS AF: 0.851 AC: 2960 AN: 3478

EpiCase AF: 0.745

EpiControl AF: 0.763

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Trichohepatoenteric syndrome 2 Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

- -

not specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0090
DANN	Benign	0.58
PhyloP100		-3.0
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	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: rs410851; hg19: chr6-31936668; COSMIC: COSV61712720; COSMIC: COSV61712720;