rs34709212

Positions:

chr2-206771993-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000402774.8(FASTKD2):c.1090G>A(p.Asp364Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,696 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 14 hom. )

Consequence

FASTKD2
ENST00000402774.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004054904).

BP6

Variant 2-206771993-G-A is Benign according to our data. Variant chr2-206771993-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 214347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0078 (1187/152270) while in subpopulation AFR AF= 0.0271 (1124/41552). AF 95% confidence interval is 0.0257. There are 21 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FASTKD2	NM_001136193.2 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12	ENST00000402774.8	NP_001129665.1
FASTKD2	NM_001136194.2 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12		NP_001129666.1
FASTKD2	NM_014929.4 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12		NP_055744.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASTKD2	ENST00000402774.8 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12	1	NM_001136193.2	ENSP00000385990	P1	Q9NYY8-1
FASTKD2	ENST00000236980.10 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12	1		ENSP00000236980	P1	Q9NYY8-1
FASTKD2	ENST00000403094.3 linkuse as main transcript	c.1090G>A	p.Asp364Asn	missense_variant	5/12	5		ENSP00000384929	P1	Q9NYY8-1
FASTKD2	ENST00000487777.5 linkuse as main transcript	n.1148G>A		non_coding_transcript_exon_variant	5/10	5

Frequencies

GnomAD3 genomes

AF:

0.00777

AC:

1182

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

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:

0.0000441

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00211

AC:

530

AN:

251406

Hom.:

AF XY:

0.00153

AC XY:

208

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000835

AC:

1220

AN:

1461426

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

531

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.0279

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000945

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.00780

AC:

1187

AN:

152270

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0271

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00867

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0288

AC:

127

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00264

AC:

320

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2014

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. -

Mitochondrial complex IV deficiency, nuclear type 1

Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.6

DANN

Benign

0.19

DEOGEN2

Benign

0.0029

T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.63

.;.;T

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.85

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

1.7

N;N;N

REVEL

Benign

0.023

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.22

MVP

0.26

MPC

0.16

ClinPred

0.0042

GERP RS

1.9

Varity_R

0.034

gMVP

0.25

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