chr20-36889299-C-A

Variant names:

• chr20-36889299-C-A
• rs142937976
• NM_080628.3:c.561C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_080628.3(TLDC2):​c.561C>A​(p.Ser187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,614,178 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (30 hom.)
• Consequence: TLDC2 NM_080628.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06825146).
• BP6: Variant 20-36889299-C-A is Benign according to our data. Variant chr20-36889299-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2652303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080628.3. 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
	TLDC2	NM_080628.3	MANE Select	c.561C>A	p.Ser187Arg	missense	Exon 6 of 7	NP_542195.1	A0PJX2
	TLDC2	NM_001304783.1		c.465C>A	p.Ser155Arg	missense	Exon 5 of 6	NP_001291712.1	A0PJX2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLDC2	ENST00000217320.8	TSL:1 MANE Select	c.561C>A	p.Ser187Arg	missense	Exon 6 of 7	ENSP00000217320.3	A0PJX2
	TLDC2	ENST00000602922.5	TSL:1	c.561C>A	p.Ser187Arg	missense	Exon 6 of 6	ENSP00000473323.1	A0PJX2
	TLDC2	ENST00000866646.1		c.561C>A	p.Ser187Arg	missense	Exon 6 of 7	ENSP00000536705.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00271 AC: 680 AN: 251310 AF XY: 0.00264

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00475 AC: 6938 AN: 1461858 Hom.: 30 Cov.: 30 AF XY: 0.00468 AC XY: 3406 AN XY: 727228

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.000850 AC: 38 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86254

European-Finnish (FIN) AF: 0.00193 AC: 103 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00573 AC: 6374 AN: 1111994

Other (OTH) AF: 0.00392 AC: 237 AN: 60396

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74482

African (AFR) AF: 0.00111 AC: 46 AN: 41578

American (AMR) AF: 0.00111 AC: 17 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00526 AC: 358 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00420 Hom.: 3

Bravo AF: 0.00266

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00450

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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		0.21
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.81		Gain of solvent accessibility (P = 0.0365)
MVP		0.71
MPC		0.35
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.95
gMVP		0.82
Mutation Taster		=87/13	polymorphism

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

dbSNP: rs142937976; hg19: chr20-35517702;