rs149250098

chr2-206767049-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136193.2(FASTKD2):c.356C>T(p.Ser119Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,613,900 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: FASTKD2 NM_001136193.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.215

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029826194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.356C>T	p.Ser119Phe	missense_variant	2/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.356C>T	p.Ser119Phe	missense_variant	2/12
FASTKD2	NM_014929.4	c.356C>T	p.Ser119Phe	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.356C>T	p.Ser119Phe	missense_variant	2/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000957 AC: 24 AN: 250882 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461696 Hom.: 1 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000899 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	Identified in the compound heterozygous state with another FASKD2 variant in a patient with myopathy in published literature (Nogueira et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30831263) -

Combined oxidative phosphorylation deficiency 44 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.5
Dann	Benign	0.51
DEOGEN2	Benign	0.0027	T;T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.047	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.98	T;T;T;T
Sift4G	Benign	0.58	T;D;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.081
MVP		0.20
MPC		0.18
ClinPred		0.017	T
GERP RS		1.3
Varity_R		0.066
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs149250098; hg19: chr2-207631773;