2-206766842-A-G

Variant names:

• chr2-206766842-A-G
• rs141447598
• NM_001136193.2:c.149A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.611
• Publications: 6 publications found

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

ACMG classification

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

Selected	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
	FASTKD2	NM_001136194.2		c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	NP_001129666.1
	FASTKD2	NM_014929.4		c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	NP_055744.2

Ensembl Transcripts

Selected	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
	FASTKD2	ENST00000236980.10	TSL:1	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	ENSP00000236980.6
	FASTKD2	ENST00000403094.3	TSL:5	c.149A>G	p.Lys50Arg	missense	Exon 2 of 12	ENSP00000384929.3

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152212 Hom.: 2 Cov.: 33

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

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.: 13 Cov.: 32 AF XY: 0.00400 AC XY: 2896 AN XY: 723940

African (AFR) AF: 0.000331 AC: 11 AN: 33214

American (AMR) AF: 0.00170 AC: 75 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.0000770 AC: 2 AN: 25966

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39602

South Asian (SAS) AF: 0.000678 AC: 58 AN: 85504

European-Finnish (FIN) AF: 0.00440 AC: 235 AN: 53358

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.00486 AC: 5391 AN: 1109166

Other (OTH) AF: 0.00339 AC: 204 AN: 60154

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152330 Hom.: 2 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74490

African (AFR) AF: 0.000866 AC: 36 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00467 AC: 318 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00250 AC: 304

EpiCase AF: 0.00442

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FASTKD2 p.Lys50Arg variant was identified in 1 of 70 proband chromosomes (frequency: 0.0143) from individuals with ataxia (Pyle_2014_PMID: 25497598). The variant was identified in dbSNP (ID: rs141447598) and ClinVar (classified as likely benign by GeneDx and Invitae, and as uncertain significance by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, CeGaT Praxis fuer Humangenetik Tuebingen, and Mayo Clinic). The variant was identified in control databases in 761 of 279634 chromosomes (2 homozygous) at a frequency of 0.002721 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 114 of 25062 chromosomes (freq: 0.004549), European (non-Finnish) in 535 of 128174 chromosomes (freq: 0.004174), Other in 23 of 7130 chromosomes (freq: 0.003226), Latino in 53 of 34698 chromosomes (freq: 0.001527), African in 17 of 24846 chromosomes (freq: 0.000684), South Asian in 15 of 29724 chromosomes (freq: 0.000505), Ashkenazi Jewish in 2 of 10180 chromosomes (freq: 0.000197), and East Asian in 2 of 19820 chromosomes (freq: 0.000101). The p.Lys50 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Oct 25, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 25, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FASTKD2: BP4, BS2

Dec 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25842392, 25842391, 25497598)

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

FASTKD2-related disorder Benign:1

May 11, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.7
DANN	Benign	0.72
DEOGEN2	Benign	0.00019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.53	N
PhyloP100		0.61
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.020
Sift	Benign	1.0	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.079
MVP		0.26
MPC		0.13
ClinPred		0.0026	T
GERP RS		0.69
Varity_R		0.030
gMVP		0.071
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141447598; hg19: chr2-207631566;