dbSNP rs141447598: FASTKD2:p.Lys50Arg (chr2-206766842-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001136193.2(FASTKD2):c.149A>G(p.Lys50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,609,052 control chromosomes in the GnomAD database, including 15 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 13 hom. )

Consequence

FASTKD2
NM_001136193.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 0.611

Publications

6 publications found

Variant links:

Genes affected

FASTKD2 (HGNC:29160): (FAST kinase domains 2) This gene encodes a protein that is localized in the mitochondrial inner compartment and that may play a role in mitochondrial apoptosis. Nonsense mutations have been reported to result in cytochrome c oxidase deficiency. [provided by RefSeq, Oct 2008]

FASTKD2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
combined oxidative phosphorylation deficiency 44
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
FASTKD2-related infantile mitochondrial encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FASTKD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042176247).

BP6

Variant 2-206766842-A-G is Benign according to our data. Variant chr2-206766842-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376842.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (426/152330) while in subpopulation NFE AF = 0.00467 (318/68032). AF 95% confidence interval is 0.00425. There are 2 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136193.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASTKD2	NM_001136193.2	MANE Select	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	NP_001129665.1	Q9NYY8-1
FASTKD2	NM_001136194.2		c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	NP_001129666.1	Q9NYY8-1
FASTKD2	NM_014929.4		c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	NP_055744.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASTKD2	ENST00000402774.8	TSL:1 MANE Select	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	ENSP00000385990.3	Q9NYY8-1
FASTKD2	ENST00000236980.10	TSL:1	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	ENSP00000236980.6	Q9NYY8-1
FASTKD2	ENST00000403094.3	TSL:5	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	ENSP00000384929.3	Q9NYY8-1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00467

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00263

AC:

652

AN:

248234

AF XY:

0.00259

show subpopulations

Gnomad AFR exome

AF:

0.000744

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00445

Gnomad NFE exome

AF:

0.00402

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00411

AC:

5980

AN:

1456722

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

2896

AN XY:

723940

show subpopulations

African (AFR)

AF:

0.000331

AC:

AN:

33214

American (AMR)

AF:

0.00170

AC:

AN:

44008

Ashkenazi Jewish (ASJ)

AF:

0.0000770

AC:

AN:

25966

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39602

South Asian (SAS)

AF:

0.000678

AC:

AN:

85504

European-Finnish (FIN)

AF:

0.00440

AC:

235

AN:

53358

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00486

AC:

5391

AN:

1109166

Other (OTH)

AF:

0.00339

AC:

204

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

285

570

854

1139

1424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.00280

AC:

426

AN:

152330

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41580

American (AMR)

AF:

0.00131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00467

AC:

318

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00345

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00250

AC:

304

EpiCase

AF:

0.00442

EpiControl

AF:

0.00385

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

FASTKD2-related disorder (1)

Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.7

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.00019

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.48

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.53

PhyloP100

0.61

PrimateAI

Benign

0.27

PROVEAN

Benign

0.46

REVEL

Benign

0.020

Sift

Benign

1.0

Sift4G

Benign

0.74

Polyphen

0.0020

Vest4

0.079

MVP

0.26

MPC

0.13

ClinPred

0.0026

GERP RS

0.69

Varity_R

0.030

gMVP

0.071

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over