NM_001136193.2:c.1294C>T

Variant names:

• chr2-206774264-C-T
• rs118203917
• NM_001136193.2:c.1294C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001136193.2(FASTKD2):​c.1294C>T​(p.Arg432*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,459,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FASTKD2 NM_001136193.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.60
• Publications: 4 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-206774264-C-T is Pathogenic according to our data. Variant chr2-206774264-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 641.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1294C>T	p.Arg432*	stop_gained	Exon 7 of 12	NP_001129665.1
	FASTKD2	NM_001136194.2		c.1294C>T	p.Arg432*	stop_gained	Exon 7 of 12	NP_001129666.1
	FASTKD2	NM_014929.4		c.1294C>T	p.Arg432*	stop_gained	Exon 7 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.1294C>T	p.Arg432*	stop_gained	Exon 7 of 12	ENSP00000385990.3
	FASTKD2	ENST00000236980.10	TSL:1	c.1294C>T	p.Arg432*	stop_gained	Exon 7 of 12	ENSP00000236980.6
	FASTKD2	ENST00000403094.3	TSL:5	c.1294C>T	p.Arg432*	stop_gained	Exon 7 of 12	ENSP00000384929.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459648 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 726358

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39554

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1110546

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation deficiency 44 (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		2.6
Vest4		0.33
GERP RS		4.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs118203917; hg19: chr2-207638988;