chr6-31961237-A-C

Variant names:

• chr6-31961237-A-C
• rs437179
• NM_006929.5:c.640A>C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0210
• Publications: 71 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=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.

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.640A>C	p.Met214Leu	missense	Exon 8 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.640A>C	p.Met214Leu	missense	Exon 8 of 28	ENSP00000364543.2	Q15477
	SKIC2	ENST00000465703.5	TSL:1	n.793A>C		non_coding_transcript_exon	Exon 7 of 23
	SKIC2	ENST00000962078.1		c.640A>C	p.Met214Leu	missense	Exon 8 of 29	ENSP00000632137.1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118616 AN: 152038 Hom.: 46957 Cov.: 32

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

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.: 53 AF XY: 0.722 AC XY: 524472 AN XY: 726846

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

GnomAD4 genome AF: 0.780 AC: 118732 AN: 152156 Hom.: 47013 Cov.: 32 AF XY: 0.783 AC XY: 58234 AN XY: 74400

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.9
DANN	Benign	0.70
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0033	N
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.021
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.033
MutPred		0.25		Gain of catalytic residue at M214 (P = 0.0565)
MPC		0.36
ClinPred		0.00034	T
GERP RS		2.3
Varity_R		0.084
gMVP		0.16
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs437179; hg19: chr6-31929014; COSMIC: COSV64813377; COSMIC: COSV64813377;