Genetic Variant DMAC2:p.Cys159Ser (chr19-41433392-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018035.3(DMAC2):c.476G>C(p.Cys159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,156 control chromosomes in the GnomAD database, including 137,155 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 15953 hom., cov: 32)

Exomes 𝑓: 0.40 ( 121202 hom. )

Consequence

DMAC2
NM_018035.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04

Publications

49 publications found

Variant links:

Genes affected

DMAC2 (HGNC:25496): (distal membrane arm assembly component 2) Involved in mitochondrial respiratory chain complex I assembly. Colocalizes with mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

DMAC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4405366E-5).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3 link	c.476G>C	p.Cys159Ser	missense_variant	Exon 5 of 6	ENST00000221943.14	NP_060505.2	Q9NW81-1A0A024R0K4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14 link	c.476G>C	p.Cys159Ser	missense_variant	Exon 5 of 6	2	NM_018035.3	ENSP00000221943.8		Q9NW81-1

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68400

AN:

151926

Hom.:

15917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.554

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.477

Gnomad ASJ

AF:

0.384

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.446

GnomAD2 exomes

AF:

0.436

AC:

109042

AN:

249980

AF XY:

0.429

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.385

Gnomad EAS exome

AF:

0.573

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.404

AC:

589788

AN:

1461112

Hom.:

121202

Cov.:

AF XY:

0.403

AC XY:

292978

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.562

AC:

18831

AN:

33478

American (AMR)

AF:

0.538

AC:

24058

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10126

AN:

26128

East Asian (EAS)

AF:

0.541

AC:

21478

AN:

39700

South Asian (SAS)

AF:

0.414

AC:

35674

AN:

86246

European-Finnish (FIN)

AF:

0.344

AC:

18149

AN:

52824

Middle Eastern (MID)

AF:

0.394

AC:

2263

AN:

5750

European-Non Finnish (NFE)

AF:

0.391

AC:

434298

AN:

1111894

Other (OTH)

AF:

0.413

AC:

24911

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

20965

41931

62896

83862

104827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13748

27496

41244

54992

68740

<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:

0.451

AC:

68496

AN:

152044

Hom.:

15953

Cov.:

AF XY:

0.449

AC XY:

33352

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.554

AC:

22987

AN:

41456

American (AMR)

AF:

0.478

AC:

7304

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.384

AC:

1333

AN:

3468

East Asian (EAS)

AF:

0.567

AC:

2928

AN:

5160

South Asian (SAS)

AF:

0.412

AC:

1989

AN:

4824

European-Finnish (FIN)

AF:

0.339

AC:

3583

AN:

10580

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27104

AN:

67950

Other (OTH)

AF:

0.447

AC:

945

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1876

3752

5628

7504

9380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.370

Hom.:

3224

Bravo

AF:

0.466

TwinsUK

AF:

0.396

AC:

1468

ALSPAC

AF:

0.394

AC:

1520

ESP6500AA

AF:

0.558

AC:

2459

ESP6500EA

AF:

0.391

AC:

3366

ExAC

AF:

0.434

AC:

52725

Asia WGS

AF:

0.494

AC:

1720

AN:

3478

EpiCase

AF:

0.403

EpiControl

AF:

0.399

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0011

T;.;.;.;T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.088

T;T;T;T;T;T

MetaRNN

Benign

0.000024

T;T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

3.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.73

N;.;N;.;.;.

REVEL

Benign

0.057

Sift

Benign

0.14

T;.;T;.;.;.

Sift4G

Benign

0.14

T;T;T;T;T;.

Polyphen

0.0

B;.;.;B;.;.

Vest4

0.099

MutPred

0.35

Loss of stability (P = 0.0135);.;.;.;.;.;

MPC

0.21

ClinPred

0.0037

GERP RS

3.4

Varity_R

0.061

gMVP

0.57

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over