17-45024611-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001288655.2(DCAKD):c.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DCAKD NM_001288655.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.228

Genes affected

DCAKD (HGNC:26238): (dephospho-CoA kinase domain containing) Predicted to enable dephospho-CoA kinase activity. Predicted to be involved in coenzyme A biosynthetic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

NMT1 (HGNC:7857): (N-myristoyltransferase 1) Myristate, a rare 14-carbon saturated fatty acid, is cotranslationally attached by an amide linkage to the N-terminal glycine residue of cellular and viral proteins with diverse functions. N-myristoyltransferase (NMT; EC 2.3.1.97) catalyzes the transfer of myristate from CoA to proteins. N-myristoylation appears to be irreversible and is required for full expression of the biologic activities of several N-myristoylated proteins, including the alpha subunit of the signal-transducing guanine nucleotide-binding protein (G protein) GO (GNAO1; MIM 139311) (Duronio et al., 1992 [PubMed 1570339]).[supplied by OMIM, Nov 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03611061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCAKD	NM_001288655.2	c.518G>A	p.Arg173His	missense_variant	5/5	ENST00000651974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCAKD	ENST00000651974.1	c.518G>A	p.Arg173His	missense_variant	5/5		NM_001288655.2	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249184 Hom.: 0 AF XY: 0.0000816 AC XY: 11 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.518G>A (p.R173H) alteration is located in exon 5 (coding exon 4) of the DCAKD gene. This alteration results from a G to A substitution at nucleotide position 518, causing the arginine (R) at amino acid position 173 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.068	T;T;T;T;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.061	N
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.036	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	N;N;.;.;.;.
REVEL	Benign	0.055
Sift	Benign	0.61	T;T;.;.;.;.
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;.
Vest4		0.043
MutPred		0.52		Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);Loss of MoRF binding (P = 0.0143);
MVP		0.092
MPC		0.31
ClinPred		0.061	T
GERP RS		-2.2
Varity_R		0.017

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

LitVar

Other links and lift over

dbSNP: rs201376374; hg19: chr17-43101979; COSMIC: COSV60831501;