NM_018294.6:c.1267C>G

Variant names:

• chr10-100236957-G-C
• NM_018294.6:c.1267C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018294.6(CWF19L1):​c.1267C>G​(p.Pro423Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

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.1267C>G	p.Pro423Ala	missense	Exon 12 of 14	NP_060764.3
	CWF19L1	NM_001303405.2		c.856C>G	p.Pro286Ala	missense	Exon 12 of 14	NP_001290334.1	Q69YN2-3
	CWF19L1	NM_001303406.2		c.856C>G	p.Pro286Ala	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.1267C>G	p.Pro423Ala	missense	Exon 12 of 14	ENSP00000326411.6	Q69YN2-1
	CWF19L1	ENST00000950162.1		c.1267C>G	p.Pro423Ala	missense	Exon 12 of 14	ENSP00000620221.1
	CWF19L1	ENST00000950161.1		c.1264C>G	p.Pro422Ala	missense	Exon 12 of 14	ENSP00000620220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.017	D
Sift4G	Benign	0.22	T
Polyphen		0.96	D
Vest4		0.60
MutPred		0.80		Gain of catalytic residue at P423 (P = 0.1727)
MVP		0.63
MPC		0.55
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.71
Mutation Taster		=29/71	disease causing

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

hg19: chr10-101996714;