10-100236976-G-T

Position:

• chr10-100236976-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018294.6(CWF19L1):​c.1255-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,566,940 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: CWF19L1 NM_018294.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002202
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.348

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-100236976-G-T is Benign according to our data. Variant chr10-100236976-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 787543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100236976-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (322/152282) while in subpopulation NFE AF= 0.00403 (274/68026). AF 95% confidence interval is 0.00364. There are 0 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CWF19L1	NM_018294.6	c.1255-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000354105.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1255-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018294.6	P1
CWF19L1	ENST00000468709.5	c.*805-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
CWF19L1	ENST00000482452.5	c.*642-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5
CWF19L1	ENST00000478047.1	n.1410-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00169 AC: 359 AN: 212072 Hom.: 1 AF XY: 0.00180 AC XY: 205 AN XY: 113972

Gnomad AFR exome AF: 0.000381

Gnomad AMR exome AF: 0.000307

Gnomad ASJ exome AF: 0.000150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00312 AC: 4411 AN: 1414658 Hom.: 9 Cov.: 31 AF XY: 0.00308 AC XY: 2152 AN XY: 699742

Gnomad4 AFR exome AF: 0.000411

Gnomad4 AMR exome AF: 0.000389

Gnomad4 ASJ exome AF: 0.000215

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.000977

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00350

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74470

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00403

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CWF19L1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.060		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: rs185005670; hg19: chr10-101996733;