dbSNP rs776337024: DARS2:p.Ser36Gly (chr1-173825335-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018122.5(DARS2):c.106A>G(p.Ser36Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.600

Publications

1 publications found

Variant links:

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

DARS2 Gene-Disease associations (from GenCC):

leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

DARS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11194843).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DARS2	NM_018122.5	MANE Select	c.106A>G	p.Ser36Gly	missense	Exon 1 of 17	NP_060592.2
DARS2	NM_001365212.1		c.106A>G	p.Ser36Gly	missense	Exon 1 of 16	NP_001352141.1	A0A3B3IT01
DARS2	NM_001365213.2		c.106A>G	p.Ser36Gly	missense	Exon 1 of 14	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DARS2	ENST00000649689.2	MANE Select	c.106A>G	p.Ser36Gly	missense	Exon 1 of 17	ENSP00000497569.1	Q6PI48
DARS2	ENST00000647645.1		c.106A>G	p.Ser36Gly	missense	Exon 1 of 16	ENSP00000497450.1	A0A3B3ISK7
DARS2	ENST00000893356.1		c.106A>G	p.Ser36Gly	missense	Exon 1 of 16	ENSP00000563415.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251442

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.57

M_CAP

Benign

0.050

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.6

PhyloP100

0.60

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.2

REVEL

Benign

0.19

Sift

Benign

0.25

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.090

MutPred

0.30

Gain of relative solvent accessibility (P = 0.0479)

MVP

0.84

MPC

0.22

ClinPred

0.34

GERP RS

4.3

PromoterAI

-0.0022

Neutral

(source)

Varity_R

0.079

gMVP

0.55

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over