2-206765614-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136193.2(FASTKD2):c.-184C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 891,742 control chromosomes in the GnomAD database, including 13,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1536 hom., cov: 31)
  • Exomes 𝑓: 0.18 (11642 hom.)
• Consequence: FASTKD2 NM_001136193.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.307

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-206765614-C-T is Benign according to our data. Variant chr2-206765614-C-T is described in ClinVar as [Benign]. Clinvar id is 333794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.-184C>T		5_prime_UTR_variant	1/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.-199C>T		5_prime_UTR_variant	1/12
FASTKD2	NM_014929.4	c.-91C>T		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.-184C>T		5_prime_UTR_variant	1/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18925 AN: 152072 Hom.: 1531 Cov.: 31

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.177 AC: 131160 AN: 739554 Hom.: 11642 Cov.: 10 AF XY: 0.178 AC XY: 61926 AN XY: 348556

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.0872

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.124 AC: 18940 AN: 152188 Hom.: 1536 Cov.: 31 AF XY: 0.124 AC XY: 9218 AN XY: 74404

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.120

Alfa AF: 0.132 Hom.: 181

Bravo AF: 0.116

Asia WGS AF: 0.167 AC: 583 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3762567; hg19: chr2-207630338;