13-99866380-C-T

Variant names:

• chr13-99866380-C-T
• rs41281112
• NM_206808.5:c.775C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_206808.5(CLYBL):​c.775C>T​(p.Arg259*) 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 ClinVar as Likely benign (★). 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: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.00
• Publications: 52 publications found

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]

ENSG00000286757 (HGNC:):

CLYBL-AS3 (HGNC:56191): (CLYBL antisense RNA 3)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 13-99866380-C-T is Benign according to our data. Variant chr13-99866380-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3907742.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206808.5. 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
	CLYBL	NM_206808.5	MANE Select	c.775C>T	p.Arg259*	stop_gained	Exon 6 of 9	NP_996531.1	Q8N0X4-1
	CLYBL	NM_001393356.1		c.775C>T	p.Arg259*	stop_gained	Exon 6 of 9	NP_001380285.1	Q8N0X4-1
	CLYBL	NM_001393357.1		c.775C>T	p.Arg259*	stop_gained	Exon 6 of 8	NP_001380286.1	Q8N0X4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLYBL	ENST00000339105.9	TSL:1 MANE Select	c.775C>T	p.Arg259*	stop_gained	Exon 6 of 9	ENSP00000342991.4	Q8N0X4-1
	CLYBL	ENST00000933047.1		c.775C>T	p.Arg259*	stop_gained	Exon 6 of 10	ENSP00000603106.1
	CLYBL	ENST00000898531.1		c.808C>T	p.Arg270*	stop_gained	Exon 6 of 9	ENSP00000568590.1

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

GnomAD2 exomes AF: 0.0283 AC: 7097 AN: 250828 AF XY: 0.0280

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 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

African (AFR) AF: 0.00508 AC: 170 AN: 33446

American (AMR) AF: 0.0290 AC: 1294 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.0471 AC: 1230 AN: 26118

East Asian (EAS) AF: 0.0451 AC: 1790 AN: 39700

South Asian (SAS) AF: 0.0239 AC: 2056 AN: 86150

European-Finnish (FIN) AF: 0.0349 AC: 1862 AN: 53416

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5760

European-Non Finnish (NFE) AF: 0.0260 AC: 28901 AN: 1111866

Other (OTH) AF: 0.0285 AC: 1720 AN: 60382

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

African (AFR) AF: 0.00527 AC: 219 AN: 41548

American (AMR) AF: 0.0338 AC: 517 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3470

East Asian (EAS) AF: 0.0430 AC: 223 AN: 5184

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4820

European-Finnish (FIN) AF: 0.0369 AC: 391 AN: 10598

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1762 AN: 68032

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0256 Hom.: 237

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.0
Vest4		0.31
GERP RS		0.12
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=53/147	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41281112; hg19: chr13-100518634;