rs148171062

Variant names:

• chr9-128947118-C-T
• rs148171062
• NM_014908.4:c.186G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014908.4(DOLK):​c.186G>A​(p.Arg62Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,614,016 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). Synonymous variant affecting the same amino acid position (i.e. R62R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (16 hom.)
• Consequence: DOLK NM_014908.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.0120
• Publications: 1 publications found

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

ENSG00000251184 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-128947118-C-T is Benign according to our data. Variant chr9-128947118-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95644.
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00272 (414/152272) while in subpopulation NFE AF = 0.00266 (181/68022). AF 95% confidence interval is 0.00234. There are 3 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.186G>A	p.Arg62Arg	synonymous	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.186G>A	p.Arg62Arg	synonymous	Exon 1 of 1	ENSP00000361667.3	Q9UPQ8
	ENSG00000251184	ENST00000482796.1	TSL:2	c.39-2071C>T		intron	N/A	ENSP00000417556.2	H7C4K7

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152154 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00333 AC: 836 AN: 251194 AF XY: 0.00333

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00281 AC: 4105 AN: 1461744 Hom.: 16 Cov.: 31 AF XY: 0.00268 AC XY: 1946 AN XY: 727180

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0203 AC: 1079 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00256 AC: 2843 AN: 1112008

Other (OTH) AF: 0.00275 AC: 166 AN: 60396

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152272 Hom.: 3 Cov.: 31 AF XY: 0.00352 AC XY: 262 AN XY: 74444

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0204 AC: 217 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	DK1-congenital disorder of glycosylation (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DOLK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.012
PromoterAI		0.0086	Neutral
Mutation Taster		=98/2	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: rs148171062; hg19: chr9-131709397;