rs116297724

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001136193.2(FASTKD2):c.-51A>G variant causes a splice region 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. 3/3 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

Scores

Splicing: ADA: 0.0004047

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.16

Publications

5 publications found

Variant links:

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

FASTKD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FASTKD2	NM_001136193.2 link	c.-51A>G	splice_region_variant	Exon 1 of 12	ENST00000402774.8	NP_001129665.1
FASTKD2	NM_001136193.2 link	c.-51A>G	5_prime_UTR_variant	Exon 1 of 12	ENST00000402774.8	NP_001129665.1
FASTKD2	NM_001136194.2 link	c.-66A>G	5_prime_UTR_variant	Exon 1 of 12		NP_001129666.1
FASTKD2	NM_014929.4 link	c.-51+93A>G	intron_variant	Intron 1 of 11		NP_055744.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASTKD2	ENST00000402774.8 link	c.-51A>G		splice_region_variant	Exon 1 of 12	1	NM_001136193.2	ENSP00000385990.3
FASTKD2	ENST00000402774.8 link	c.-51A>G		5_prime_UTR_variant	Exon 1 of 12	1	NM_001136193.2	ENSP00000385990.3

Frequencies

GnomAD3 genomes

AF:

0.00892

AC:

1357

AN:

152102

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0139

AC XY:

AN XY:

3876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

176

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

348

European-Finnish (FIN)

AF:

0.0200

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0154

AC:

103

AN:

6672

Other (OTH)

AF:

0.0106

AC:

AN:

284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00890

AC:

1355

AN:

152220

Hom.:

Cov.:

AF XY:

0.00981

AC XY:

730

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41542

American (AMR)

AF:

0.00431

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0335

AC:

355

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0125

AC:

849

AN:

68020

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00631

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 21, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 23, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FASTKD2: BS1, BS2 -

May 06, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined oxidative phosphorylation deficiency 44

Benign:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.8

(source)

DANN

Benign

0.60

PhyloP100

-1.2

PromoterAI

-0.056

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over