rs780598300

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_018706.7(DHTKD1):c.626C>T(p.Ser209Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S209S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DHTKD1
NM_018706.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.00

Publications

0 publications found

Variant links:

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

DHTKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2744598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHTKD1	NM_018706.7 link	c.626C>T	p.Ser209Leu	missense_variant	Exon 4 of 17	ENST00000263035.9	NP_061176.4	Q96HY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DHTKD1	ENST00000263035.9 link	c.626C>T	p.Ser209Leu	missense_variant	Exon 4 of 17	1	NM_018706.7	ENSP00000263035.4	Q96HY7
DHTKD1	ENST00000465617.1 link	n.208C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
DHTKD1	ENST00000437298.1 link	c.523-1348C>T		intron_variant	Intron 3 of 4	3		ENSP00000388163.1	C9JWN1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251250

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000176

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111964

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 19, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

2-aminoadipic 2-oxoadipic aciduria

Uncertain:1

Aug 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 520868). This variant has not been reported in the literature in individuals affected with DHTKD1-related conditions. This variant is present in population databases (rs780598300, ExAC 0.05%). This sequence change replaces serine with leucine at codon 209 of the DHTKD1 protein (p.Ser209Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0073

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.11

Sift

Uncertain

0.018

Sift4G

Benign

0.074

Polyphen

0.12

Vest4

0.54

MVP

0.28

MPC

0.11

ClinPred

0.080

GERP RS

4.4

Varity_R

0.50

gMVP

0.83

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over