Genetic Variant NM_001136193.2:c.29G>C (chr2-206766722-G-C) – 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.29G>C(p.Ser10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,614,110 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S10N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 41 hom. )

Consequence

FASTKD2
NM_001136193.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.28

Publications

11 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=0.0048784614).

BP6

Variant 2-206766722-G-C is Benign according to our data. Variant chr2-206766722-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137293.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00453 (690/152322) while in subpopulation NFE AF = 0.00801 (545/68028). AF 95% confidence interval is 0.00745. There are 3 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.29G>C	p.Ser10Thr	missense	Exon 2 of 12	NP_001129665.1	Q9NYY8-1
FASTKD2	NM_001136194.2		c.29G>C	p.Ser10Thr	missense	Exon 2 of 12	NP_001129666.1	Q9NYY8-1
FASTKD2	NM_014929.4		c.29G>C	p.Ser10Thr	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.29G>C	p.Ser10Thr	missense	Exon 2 of 12	ENSP00000385990.3	Q9NYY8-1
FASTKD2	ENST00000236980.10	TSL:1	c.29G>C	p.Ser10Thr	missense	Exon 2 of 12	ENSP00000236980.6	Q9NYY8-1
FASTKD2	ENST00000403094.3	TSL:5	c.29G>C	p.Ser10Thr	missense	Exon 2 of 12	ENSP00000384929.3	Q9NYY8-1

Frequencies

GnomAD3 genomes

AF:

0.00453

AC:

690

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00801

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00403

AC:

1012

AN:

251280

AF XY:

0.00387

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00744

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00714

AC:

10431

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

4934

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00206

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00168

AC:

145

AN:

86254

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00881

AC:

9799

AN:

1111952

Other (OTH)

AF:

0.00450

AC:

272

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

492

984

1476

1968

2460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.00453

AC:

690

AN:

152322

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

41580

American (AMR)

AF:

0.00268

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00801

AC:

545

AN:

68028

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00585

Hom.:

Bravo

AF:

0.00441

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00429

AC:

521

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.30

M_CAP

Benign

0.019

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

2.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.42

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Sift4G

Benign

0.19

Polyphen

0.81

Vest4

0.15

MVP

0.60

MPC

0.18

ClinPred

0.022

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.18

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

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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