2-206766842-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001136193.2(FASTKD2):ā€‹c.149A>Gā€‹(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. 15/21 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: š‘“ 0.0028 ( 2 hom., cov: 33)
Exomes š‘“: 0.0041 ( 13 hom. )

Consequence

FASTKD2
NM_001136193.2 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: 0.611
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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 id is 376842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr2-206766842-A-G is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FASTKD2NM_001136193.2 linkuse as main transcriptc.149A>G p.Lys50Arg missense_variant 2/12 ENST00000402774.8 NP_001129665.1 Q9NYY8-1A0A024R3X5
FASTKD2NM_001136194.2 linkuse as main transcriptc.149A>G p.Lys50Arg missense_variant 2/12 NP_001129666.1 Q9NYY8-1A0A024R3X5
FASTKD2NM_014929.4 linkuse as main transcriptc.149A>G p.Lys50Arg missense_variant 2/12 NP_055744.2 Q9NYY8-1A0A024R3X5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FASTKD2ENST00000402774.8 linkuse as main transcriptc.149A>G p.Lys50Arg missense_variant 2/121 NM_001136193.2 ENSP00000385990.3 Q9NYY8-1

Frequencies

GnomAD3 genomes
AF:
0.00279
AC:
424
AN:
152212
Hom.:
2
Cov.:
33
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
GnomAD3 exomes
AF:
0.00263
AC:
652
AN:
248234
Hom.:
2
AF XY:
0.00259
AC XY:
348
AN XY:
134154
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 SAS exome
AF:
0.000505
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000331
Gnomad4 AMR exome
AF:
0.00170
Gnomad4 ASJ exome
AF:
0.0000770
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.000678
Gnomad4 FIN exome
AF:
0.00440
Gnomad4 NFE exome
AF:
0.00486
Gnomad4 OTH exome
AF:
0.00339
GnomAD4 genome
AF:
0.00280
AC:
426
AN:
152330
Hom.:
2
Cov.:
33
AF XY:
0.00239
AC XY:
178
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000866
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00414
Gnomad4 NFE
AF:
0.00467
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00347
Hom.:
0
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:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 10, 2019This variant is associated with the following publications: (PMID: 25842392, 25842391, 25497598) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024FASTKD2: BP4, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 25, 2016- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Uncertain significance, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 25, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024- -
Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 11, 2021This 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 v4.3

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;T;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.48
.;T;.;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.0042
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.53
N;.;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.46
N;N;N;N
REVEL
Benign
0.020
Sift
Benign
1.0
T;T;T;T
Sift4G
Benign
0.74
T;T;T;T
Polyphen
0.0020
B;.;B;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141447598; hg19: chr2-207631566; API