chr2-206791762-C-T

Position:

chr2-206791762-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001136193.2(FASTKD2):c.2093C>T(p.Ala698Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,612,818 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

FASTKD2
NM_001136193.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.261

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029308498).

BP6

Variant 2-206791762-C-T is Benign according to our data. Variant chr2-206791762-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214346.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00229 (348/152290) while in subpopulation AFR AF= 0.0079 (328/41542). AF 95% confidence interval is 0.00719. There are 2 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FASTKD2	NM_001136193.2 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12	ENST00000402774.8
FASTKD2	NM_001136194.2 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12
FASTKD2	NM_014929.4 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12	1	NM_001136193.2	P1	Q9NYY8-1
FASTKD2	ENST00000236980.10 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12	1		P1	Q9NYY8-1
FASTKD2	ENST00000403094.3 linkuse as main transcript	c.2093C>T	p.Ala698Val	missense_variant	12/12	5		P1	Q9NYY8-1
FASTKD2	ENST00000487777.5 linkuse as main transcript	n.4815C>T		non_coding_transcript_exon_variant	10/10	5

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

348

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00792

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000642

AC:

161

AN:

250886

Hom.:

AF XY:

0.000531

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00843

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000240

AC:

351

AN:

1460528

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

726654

show subpopulations

Gnomad4 AFR exome

AF:

0.00811

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.00229

AC:

348

AN:

152290

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00790

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000423

Hom.:

Bravo

AF:

0.00267

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000914

AC:

111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	- -

Mitochondrial complex IV deficiency, nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.0

DANN

Benign

0.90

DEOGEN2

Benign

0.0059

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.44

.;.;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.0080

Sift

Benign

0.50

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.024

B;B;B

Vest4

0.040

MVP

0.13

MPC

0.16

ClinPred

0.0036

GERP RS

0.77

Varity_R

0.019

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over