2-206766737-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136193.2(FASTKD2):c.44G>A(p.Ser15Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 1,613,708 control chromosomes in the GnomAD database, including 7,451 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S15G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1539 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5912 hom.)
• Consequence: FASTKD2 NM_001136193.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0400

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 (MetaRNN=0.004671097).
• BP6: Variant 2-206766737-G-A is Benign according to our data. Variant chr2-206766737-G-A is described in ClinVar as [Benign]. Clinvar id is 333800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-206766737-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.44G>A	p.Ser15Asn	missense_variant	2/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.44G>A	p.Ser15Asn	missense_variant	2/12
FASTKD2	NM_014929.4	c.44G>A	p.Ser15Asn	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.44G>A	p.Ser15Asn	missense_variant	2/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18123 AN: 152078 Hom.: 1528 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0761

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0470

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0795 AC: 19976 AN: 251196 Hom.: 1140 AF XY: 0.0783 AC XY: 10635 AN XY: 135794

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.0412

Gnomad EAS exome AF: 0.0401

Gnomad SAS exome AF: 0.0882

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.0761

GnomAD4 exome AF: 0.0832 AC: 121647 AN: 1461510 Hom.: 5912 Cov.: 32 AF XY: 0.0825 AC XY: 59991 AN XY: 727064

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.0417

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.0901

Gnomad4 FIN exome AF: 0.0578

Gnomad4 NFE exome AF: 0.0824

Gnomad4 OTH exome AF: 0.0880

GnomAD4 genome AF: 0.119 AC: 18171 AN: 152198 Hom.: 1539 Cov.: 33 AF XY: 0.116 AC XY: 8665 AN XY: 74406

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.0758

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.0468

Gnomad4 SAS AF: 0.0880

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0891 Hom.: 868

Bravo AF: 0.126

TwinsUK AF: 0.0844 AC: 313

ALSPAC AF: 0.0737 AC: 284

ESP6500AA AF: 0.244 AC: 1075

ESP6500EA AF: 0.0758 AC: 652

ExAC AF: 0.0842 AC: 10217

Asia WGS AF: 0.0830 AC: 289 AN: 3478

EpiCase AF: 0.0788

EpiControl AF: 0.0798

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.5
Dann	Benign	0.97
DEOGEN2	Benign	0.0037	T;T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.0050	B;.;B;B
Vest4		0.018
MPC		0.15
ClinPred		0.011	T
GERP RS		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.13

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

Other links and lift over

dbSNP: rs3762568; hg19: chr2-207631461; COSMIC: COSV52698601; COSMIC: COSV52698601;