2-206766694-A-T

Position:

• chr2-206766694-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001136193.2(FASTKD2):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,710 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FASTKD2 NM_001136193.2 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0850

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASTKD2	NM_001136193.2	c.1A>T	p.Met1?	initiator_codon_variant	2/12	ENST00000402774.8	NP_001129665.1
FASTKD2	NM_001136194.2	c.1A>T	p.Met1?	initiator_codon_variant	2/12		NP_001129666.1
FASTKD2	NM_014929.4	c.1A>T	p.Met1?	initiator_codon_variant	2/12		NP_055744.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASTKD2	ENST00000402774.8	c.1A>T	p.Met1?	initiator_codon_variant	2/12	1	NM_001136193.2	ENSP00000385990.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 44 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.4
DANN	Benign	0.82
DEOGEN2	Benign	0.00018	T;T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Benign	0.0052	T
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.23
MutPred		0.99		Loss of methylation at K6 (P = 0.0545);Loss of methylation at K6 (P = 0.0545);Loss of methylation at K6 (P = 0.0545);Loss of methylation at K6 (P = 0.0545);
MVP		0.25
ClinPred		0.17	T
GERP RS		1.2
Varity_R		0.080
gMVP		0.098

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: rs1689491777; hg19: chr2-207631418;