NM_006929.5:c.640A>C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 356318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31961237-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKIC2	NM_006929.5	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 28	ENST00000375394.7	NP_008860.4
SKIC2	XM_011514815.4	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 25		XP_011513117.1
SKIC2	XM_047419259.1	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 25		XP_047275215.1
SKIC2	XM_047419260.1	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 24		XP_047275216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKIC2	ENST00000375394.7	c.640A>C	p.Met214Leu	missense_variant	Exon 8 of 28	1	NM_006929.5	ENSP00000364543.2

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

GnomAD3 exomes AF: 0.763 AC: 191158 AN: 250578 Hom.: 73945 AF XY: 0.772 AC XY: 104536 AN XY: 135486

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 SAS exome AF: 0.899

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

Gnomad4 AFR exome AF: 0.911

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.867

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.895

Gnomad4 FIN exome AF: 0.725

Gnomad4 NFE exome AF: 0.689

Gnomad4 OTH exome AF: 0.737

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

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.747

Gnomad4 ASJ AF: 0.872

Gnomad4 EAS AF: 0.681

Gnomad4 SAS AF: 0.887

Gnomad4 FIN AF: 0.741

Gnomad4 NFE AF: 0.710

Gnomad4 OTH AF: 0.820

Alfa AF: 0.733 Hom.: 84716

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

This variant is associated with the following publications: (PMID: 28173125) -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

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