dbSNP rs34709212: FASTKD2:p.Asp364Asn (chr2-206771993-G-A) – ACMG Classification: Benign (-20 pts)

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D364G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0078 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 14 hom. )

Consequence

FASTKD2
NM_001136193.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

Publications

3 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 (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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136193.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASTKD2	NM_001136193.2	MANE Select	c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	NP_001129665.1	Q9NYY8-1
FASTKD2	NM_001136194.2		c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	NP_001129666.1	Q9NYY8-1
FASTKD2	NM_014929.4		c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	NP_055744.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASTKD2	ENST00000402774.8	TSL:1 MANE Select	c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	ENSP00000385990.3	Q9NYY8-1
FASTKD2	ENST00000236980.10	TSL:1	c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	ENSP00000236980.6	Q9NYY8-1
FASTKD2	ENST00000403094.3	TSL:5	c.1090G>A	p.Asp364Asn	missense	Exon 5 of 12	ENSP00000384929.3	Q9NYY8-1

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

GnomAD2 exomes

AF:

0.00211

AC:

530

AN:

251406

AF XY:

0.00153

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 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

African (AFR)

AF:

0.0279

AC:

932

AN:

33456

American (AMR)

AF:

0.00127

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000945

AC:

105

AN:

1111656

Other (OTH)

AF:

0.00187

AC:

113

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00780

AC:

1187

AN:

152270

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0271

AC:

1124

AN:

41552

American (AMR)

AF:

0.00268

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

163

218

272

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:

0.00306

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Mitochondrial complex IV deficiency, nuclear type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.6

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.0029

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.85

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

1.7

REVEL

Benign

0.023

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.22

MVP

0.26

MPC

0.16

ClinPred

0.0042

GERP RS

1.9

Varity_R

0.034

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over