NM_018294.6:c.1283C>T

Variant names:

• chr10-100236941-G-A
• rs1333015672
• NM_018294.6:c.1283C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018294.6(CWF19L1):​c.1283C>T​(p.Thr428Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• Publications: 0 publications found

Genes affected

CWF19L1 (HGNC:25613): (CWF19 like cell cycle control factor 1) This gene encodes a member of the CWF19 protein family. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia-17 and mild cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

CHUK-DT (HGNC:55813): (CHUK divergent transcript)

SNORA12 (HGNC:32600): (small nucleolar RNA, H/ACA box 12) Small nucleolar RNAs (snoRNAs) are small noncoding RNAs involved in RNA processing. Box H/ACA snoRNAs, such as SNORA12, direct the conversion of uridine to pseudouridine at specific residues of ribosomal RNAs or small nuclear RNAs (snRNAs) (Gu et al., 2005).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098700315).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018294.6. 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
	CWF19L1	NM_018294.6	MANE Select	c.1283C>T	p.Thr428Ile	missense	Exon 12 of 14	NP_060764.3
	CWF19L1	NM_001303405.2		c.872C>T	p.Thr291Ile	missense	Exon 12 of 14	NP_001290334.1	Q69YN2-3
	CWF19L1	NM_001303406.2		c.872C>T	p.Thr291Ile	missense	Exon 9 of 11	NP_001290335.1	Q69YN2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWF19L1	ENST00000354105.10	TSL:1 MANE Select	c.1283C>T	p.Thr428Ile	missense	Exon 12 of 14	ENSP00000326411.6	Q69YN2-1
	CWF19L1	ENST00000950162.1		c.1283C>T	p.Thr428Ile	missense	Exon 12 of 14	ENSP00000620221.1
	CWF19L1	ENST00000950161.1		c.1280C>T	p.Thr427Ile	missense	Exon 12 of 14	ENSP00000620220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243544 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455284 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723778

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.0000231 AC: 1 AN: 43312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109068

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.027
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.016	B
Vest4		0.19
MutPred		0.28		Loss of catalytic residue at T428 (P = 0.0023)
MVP		0.25
MPC		0.20
ClinPred		0.096	T
GERP RS		3.3
Varity_R		0.034
gMVP		0.23
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1333015672; hg19: chr10-101996698;