10-12069096-G-C

Variant names:

• chr10-12069096-G-C
• NM_018706.7:c.63G>C
• DHTKD1 p.Trp21Cys

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018706.7(DHTKD1):​c.63G>C​(p.Trp21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHTKD1 NM_018706.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.880
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000294071 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018706.7. 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
	DHTKD1	NM_018706.7	MANE Select	c.63G>C	p.Trp21Cys	missense	Exon 1 of 17	NP_061176.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHTKD1	ENST00000263035.9	TSL:1 MANE Select	c.63G>C	p.Trp21Cys	missense	Exon 1 of 17	ENSP00000263035.4	Q96HY7
	DHTKD1	ENST00000889958.1		c.63G>C	p.Trp21Cys	missense	Exon 1 of 18	ENSP00000560017.1
	DHTKD1	ENST00000940762.1		c.63G>C	p.Trp21Cys	missense	Exon 1 of 17	ENSP00000610821.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0041	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.88
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
PromoterAI		-0.021	Neutral
Varity_R		0.11
gMVP		0.61
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-12111095;