10-12089191-G-C

Variant names:

• chr10-12089191-G-C
• rs17849603
• NM_018706.7:c.923G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018706.7(DHTKD1):​c.923G>C​(p.Arg308Pro) 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 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

Genes affected

DHTKD1 (HGNC:23537): (dehydrogenase E1 and transketolase domain containing 1) This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30608338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7	c.923G>C	p.Arg308Pro	missense_variant	Exon 5 of 17	ENST00000263035.9	NP_061176.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHTKD1	ENST00000263035.9	c.923G>C	p.Arg308Pro	missense_variant	Exon 5 of 17	1	NM_018706.7	ENSP00000263035.4
DHTKD1	ENST00000437298.1	c.728G>C	p.Arg243Pro	missense_variant	Exon 4 of 5	3		ENSP00000388163.1
DHTKD1	ENST00000415935.1	c.17G>C	p.Arg6Pro	missense_variant	Exon 1 of 3	2		ENSP00000400625.1
DHTKD1	ENST00000465617.1	n.299+1462G>C		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251362 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

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	0.61
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.58	P;.;.
Vest4		0.58
MutPred		0.55		Loss of MoRF binding (P = 0.0202);.;.;
MVP		0.66
MPC		0.35
ClinPred		0.57	D
GERP RS		3.2
Varity_R		0.89
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs17849603; hg19: chr10-12131190;