20-36889299-C-G

Variant names:

• chr20-36889299-C-G
• NM_080628.3:c.561C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080628.3(TLDC2):​c.561C>G​(p.Ser187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLDC2 NM_080628.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208

Genes affected

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLDC2	NM_080628.3	c.561C>G	p.Ser187Arg	missense_variant	Exon 6 of 7	ENST00000217320.8	NP_542195.1
TLDC2	NM_001304783.1	c.465C>G	p.Ser155Arg	missense_variant	Exon 5 of 6		NP_001291712.1
TLDC2	XM_017027674.2	c.273C>G	p.Ser91Arg	missense_variant	Exon 5 of 5		XP_016883163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLDC2	ENST00000217320.8	c.561C>G	p.Ser187Arg	missense_variant	Exon 6 of 7	1	NM_080628.3	ENSP00000217320.3
TLDC2	ENST00000602922.5	c.561C>G	p.Ser187Arg	missense_variant	Exon 6 of 6	1		ENSP00000473323.1
TLDC2	ENST00000436941.1	c.74+1771C>G		intron_variant	Intron 1 of 1	3		ENSP00000394804.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	.;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.81		Gain of solvent accessibility (P = 0.0365);Gain of solvent accessibility (P = 0.0365);
MVP		0.71
MPC		0.35
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-35517702;