rs41281112

chr13-99866380-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM4 PP5 BS1_Supporting BS2

The NM_206808.5(CLYBL):c.775C>T(p.Arg259Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,646 control chromosomes in the GnomAD database, including 708 homozygotes. Variant has been reported in Lovd as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 32)
  • Exomes 𝑓: 0.027 (647 hom.)
• Consequence: CLYBL NM_206808.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00

Genes affected

CLYBL (HGNC:18355): (citramalyl-CoA lyase) Enables (S)-citramalyl-CoA lyase activity; magnesium ion binding activity; and malate synthase activity. Involved in protein homotrimerization and regulation of cobalamin metabolic process. Predicted to be located in mitochondrion. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_206808.5 Downstream stopcodon found after 342 codons.
• PP5: Variant 13-99866380-C-T is Pathogenic according to our data. Variant chr13-99866380-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0226 (3447/152250) while in subpopulation EAS AF= 0.043 (223/5184). AF 95% confidence interval is 0.0384. There are 61 homozygotes in gnomad4. There are 1749 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLYBL	NM_206808.5	c.775C>T	p.Arg259Ter	stop_gained	6/9	ENST00000339105.9
CLYBL-AS3	NR_120421.1	n.83+90703G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLYBL	ENST00000339105.9	c.775C>T	p.Arg259Ter	stop_gained	6/9	1	NM_206808.5	P1
	ENST00000670575.1	n.86-10936G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3446 AN: 152132 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0427

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0283 AC: 7097 AN: 250828 Hom.: 121 AF XY: 0.0280 AC XY: 3794 AN XY: 135574

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.0491

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0268 AC: 39223 AN: 1461396 Hom.: 647 Cov.: 33 AF XY: 0.0268 AC XY: 19470 AN XY: 727000

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.0471

Gnomad4 EAS exome AF: 0.0451

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.0349

Gnomad4 NFE exome AF: 0.0260

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0226 AC: 3447 AN: 152250 Hom.: 61 Cov.: 32 AF XY: 0.0235 AC XY: 1749 AN XY: 74440

Gnomad4 AFR AF: 0.00527

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.0430

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0264 Hom.: 104

Bravo AF: 0.0217

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0283 AC: 243

ExAC AF: 0.0273 AC: 3315

EpiCase AF: 0.0224

EpiControl AF: 0.0251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Benign	0.96
Eigen	Benign	0.097
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.60	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.31
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs41281112; hg19: chr13-100518634;