2-206766722-G-C

Position:

• chr2-206766722-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001136193.2(FASTKD2):​c.29G>C​(p.Ser10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,614,110 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S10N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (41 hom.)
• Consequence: FASTKD2 NM_001136193.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.28

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048784614).
• BP6: Variant 2-206766722-G-C is Benign according to our data. Variant chr2-206766722-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137293.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr2-206766722-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00453 (690/152322) while in subpopulation NFE AF= 0.00801 (545/68028). AF 95% confidence interval is 0.00745. There are 3 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.29G>C	p.Ser10Thr	missense_variant	2/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.29G>C	p.Ser10Thr	missense_variant	2/12
FASTKD2	NM_014929.4	c.29G>C	p.Ser10Thr	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.29G>C	p.Ser10Thr	missense_variant	2/12	1	NM_001136193.2	P1

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00801

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00403 AC: 1012 AN: 251280 Hom.: 4 AF XY: 0.00387 AC XY: 526 AN XY: 135870

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00714 AC: 10431 AN: 1461788 Hom.: 41 Cov.: 31 AF XY: 0.00678 AC XY: 4934 AN XY: 727194

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00881

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.00453 AC: 690 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74478

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00801

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00585 Hom.: 6

Bravo AF: 0.00441

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00429 AC: 521

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FASTKD2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 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 Uncertain:1

Uncertain significance, 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, 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. -

FASTKD2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0022	T;T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.30	.;T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N;N;N;N
REVEL	Benign	0.039
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.19	T;D;T;T
Polyphen		0.81	P;.;P;P
Vest4		0.15
MVP		0.60
MPC		0.18
ClinPred		0.022	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.18

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: rs147727753; hg19: chr2-207631446;