rs145310298

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014908.4(DOLK):c.631C>T(p.Arg211Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,128 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 17 hom. )

Consequence

DOLK
NM_014908.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 3.35

Publications

12 publications found

Variant links:

Genes affected

DOLK (HGNC:23406): (dolichol kinase) The protein encoded by this gene catalyzes the CTP-mediated phosphorylation of dolichol, and is involved in the synthesis of Dol-P-Man, which is an essential glycosyl carrier lipid for C- and O-mannosylation, N- and O-linked glycosylation of proteins, and for the biosynthesis of glycosyl phosphatidylinositol anchors in endoplasmic reticulum. Mutations in this gene are associated with dolichol kinase deficiency.[provided by RefSeq, Apr 2010]

DOLK Gene-Disease associations (from GenCC):

DK1-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DOLK links:

ENSG00000251184 (HGNC:):

ENSG00000251184 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015254825).

BP6

Variant 9-128946673-G-A is Benign according to our data. Variant chr9-128946673-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95646.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00233 (354/152238) while in subpopulation AMR AF = 0.0036 (55/15276). AF 95% confidence interval is 0.00315. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014908.4. 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
	DOLK	NM_014908.4	MANE Select	c.631C>T	p.Arg211Cys	missense	Exon 1 of 1	NP_055723.1	Q9UPQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOLK	ENST00000372586.4	TSL:6 MANE Select	c.631C>T	p.Arg211Cys	missense	Exon 1 of 1	ENSP00000361667.3	Q9UPQ8
	ENSG00000251184	ENST00000482796.1	TSL:2	c.39-2516G>A		intron	N/A	ENSP00000417556.2	H7C4K7

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

355

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00351

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00189

AC:

476

AN:

251394

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00281

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00342

AC:

5003

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

2417

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.00219

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000962

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00409

AC:

4548

AN:

1112012

Other (OTH)

AF:

0.00359

AC:

217

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

344

688

1031

1375

1719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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

AF:

0.00233

AC:

354

AN:

152238

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41538

American (AMR)

AF:

0.00360

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00351

AC:

239

AN:

68010

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00226

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

DK1-congenital disorder of glycosylation (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.17

Eigen

Benign

-0.030

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.036

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.1

PhyloP100

3.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.49

REVEL

Uncertain

0.59

Sift

Benign

0.18

Sift4G

Benign

0.15

Polyphen

0.59

Vest4

0.24

MVP

0.85

MPC

0.51

ClinPred

0.014

GERP RS

4.4

Varity_R

0.067

gMVP

0.60

Mutation Taster

=55/45

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over