rs116297724

chr2-206765747-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001136193.2(FASTKD2):c.-51A>G variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 159,928 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (11 hom., cov: 31)
  • Exomes 𝑓: 0.014 (2 hom.)
• Consequence: FASTKD2 NM_001136193.2 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.0004047
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.16

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=-0.8).
• BP6: Variant 2-206765747-A-G is Benign according to our data. Variant chr2-206765747-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0089 (1355/152220) while in subpopulation NFE AF= 0.0125 (849/68020). AF 95% confidence interval is 0.0118. There are 11 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.-51A>G		splice_region_variant, 5_prime_UTR_variant	1/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.-66A>G		5_prime_UTR_variant	1/12
FASTKD2	NM_014929.4	c.-51+93A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.-51A>G		splice_region_variant, 5_prime_UTR_variant	1/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152102 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.0139 AC: 107 AN: 7708 Hom.: 2 Cov.: 4 AF XY: 0.0139 AC XY: 54 AN XY: 3876

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: 0.0200

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00890 AC: 1355 AN: 152220 Hom.: 11 Cov.: 31 AF XY: 0.00981 AC XY: 730 AN XY: 74420

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.0115 Hom.: 2

Bravo AF: 0.00631

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FASTKD2: BS1, BS2 -

Combined oxidative phosphorylation deficiency 44 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.8
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.15		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: rs116297724; hg19: chr2-207630471;