rs8875

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBA1

The NM_004549.6(NDUFC2):c.136C>G(p.Leu46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,561,654 control chromosomes in the GnomAD database, including 38,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.18 ( 2950 hom., cov: 31)

Exomes 𝑓: 0.22 ( 35854 hom. )

Consequence

NDUFC2
NM_004549.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0690

Publications

29 publications found

Variant links:

Genes affected

NDUFC2 (HGNC:7706): (NADH:ubiquinone oxidoreductase subunit C2) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency. [provided by Alliance of Genome Resources, Apr 2022]

NDUFC2 links:

NDUFC2-KCTD14 (HGNC:42956): (NDUFC2-KCTD14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NDUFC2 (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa) and KCTD14 (potassium channel tetramerisation domain containing 14) genes on chromosome 11. The read-through transcripts share sequence identity with the upstream gene product and one variant has a frameshifted C-terminal region derived from the downstream gene exons. [provided by RefSeq, Feb 2011]

NDUFC2-KCTD14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.23764 (below the threshold of 3.09). Trascript score misZ: -0.065329 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial disease, Leigh syndrome, mitochondrial complex I deficiency, nuclear type 36.

BP4

Computational evidence support a benign effect (MetaRNN=0.005250782).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFC2	NM_004549.6 link	c.136C>G	p.Leu46Val	missense_variant	Exon 1 of 3	ENST00000281031.5	NP_004540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFC2	ENST00000281031.5 link	c.136C>G	p.Leu46Val	missense_variant	Exon 1 of 3	1	NM_004549.6	ENSP00000281031.4
NDUFC2-KCTD14	ENST00000530054.1 link	c.136C>G	p.Leu46Val	missense_variant	Exon 1 of 3	2		ENSP00000432614.1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27178

AN:

152054

Hom.:

2947

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0623

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.0729

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.235

Gnomad OTH

AF:

0.203

GnomAD2 exomes

AF:

0.202

AC:

33765

AN:

167340

AF XY:

0.205

show subpopulations

Gnomad AFR exome

AF:

0.0584

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.309

Gnomad EAS exome

AF:

0.0816

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.221

AC:

312071

AN:

1409482

Hom.:

35854

Cov.:

AF XY:

0.222

AC XY:

154302

AN XY:

696332

show subpopulations

African (AFR)

AF:

0.0584

AC:

1879

AN:

32180

American (AMR)

AF:

0.220

AC:

8071

AN:

36734

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7710

AN:

25252

East Asian (EAS)

AF:

0.0677

AC:

2493

AN:

36812

South Asian (SAS)

AF:

0.197

AC:

15756

AN:

80182

European-Finnish (FIN)

AF:

0.184

AC:

9174

AN:

49834

Middle Eastern (MID)

AF:

0.263

AC:

1230

AN:

4684

European-Non Finnish (NFE)

AF:

0.233

AC:

253195

AN:

1085506

Other (OTH)

AF:

0.215

AC:

12563

AN:

58298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16263

32526

48788

65051

81314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8638

17276

25914

34552

43190

<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:

0.179

AC:

27190

AN:

152172

Hom.:

2950

Cov.:

AF XY:

0.178

AC XY:

13213

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0621

AC:

2580

AN:

41560

American (AMR)

AF:

0.235

AC:

3585

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1044

AN:

3470

East Asian (EAS)

AF:

0.0736

AC:

380

AN:

5160

South Asian (SAS)

AF:

0.198

AC:

956

AN:

4822

European-Finnish (FIN)

AF:

0.190

AC:

2017

AN:

10596

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.235

AC:

15979

AN:

67972

Other (OTH)

AF:

0.200

AC:

422

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1114

2227

3341

4454

5568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.232

Hom.:

1416

Bravo

AF:

0.176

TwinsUK

AF:

0.231

AC:

858

ALSPAC

AF:

0.246

AC:

950

ESP6500AA

AF:

0.0708

AC:

308

ESP6500EA

AF:

0.219

AC:

1859

ExAC

AF:

0.170

AC:

19507

Asia WGS

AF:

0.135

AC:

468

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.013

T;T;.;.;T;.;T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.20

T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0053

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;.;.;.;.;.;.;.

PhyloP100

0.069

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.21

N;N;.;.;N;N;N;N;N

REVEL

Benign

0.020

Sift

Benign

0.20

T;T;.;.;T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T;T;T;T;T

Polyphen

0.0030

.;.;.;.;B;.;.;.;.

Vest4

0.11

MPC

0.58, 0.56

ClinPred

0.0090

GERP RS

-0.89

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.092

gMVP

0.34

Mutation Taster

=95/5

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