NM_018706.7:c.923G>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018706.7(DHTKD1):​c.923G>T​(p.Arg308Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R308C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 6 publications found

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]

DHTKD1 Gene-Disease associations (from GenCC):

• 2-aminoadipic 2-oxoadipic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Charcot-Marie-Tooth disease axonal type 2Q

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05337873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7	c.923G>T	p.Arg308Leu	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>T	p.Arg308Leu	missense_variant	Exon 5 of 17	1	NM_018706.7	ENSP00000263035.4
DHTKD1	ENST00000437298.1	c.728G>T	p.Arg243Leu	missense_variant	Exon 4 of 5	3		ENSP00000388163.1
DHTKD1	ENST00000415935.1	c.17G>T	p.Arg6Leu	missense_variant	Exon 1 of 3	2		ENSP00000400625.1
DHTKD1	ENST00000465617.1	n.299+1462G>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	11
DANN	Benign	0.12
DEOGEN2	Benign	0.045	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.29	N;.;.
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.20
MutPred		0.49		Loss of MoRF binding (P = 0.0366);.;.;
MVP		0.27
MPC		0.14
ClinPred		0.059	T
GERP RS		3.2
PromoterAI		0.0027	Neutral
Varity_R		0.14
gMVP		0.54
Mutation Taster		=84/16	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: rs17849603; hg19: chr10-12131190;