2-206765668-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001136193.2(FASTKD2):c.-130G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000966 in 355,090 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: FASTKD2 NM_001136193.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.423

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-206765668-G-A is Benign according to our data. Variant chr2-206765668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333796.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.-130G>A		5_prime_UTR_variant	1/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.-145G>A		5_prime_UTR_variant	1/12
FASTKD2	NM_014929.4	c.-51+14G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.-130G>A		5_prime_UTR_variant	1/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00110 AC: 224 AN: 202954 Hom.: 1 Cov.: 5 AF XY: 0.00131 AC XY: 127 AN XY: 97166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000540

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.000767 AC XY: 57 AN XY: 74298

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000827

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.1
Dann	Benign	0.87

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

Other links and lift over

dbSNP: rs543042440; hg19: chr2-207630392;