rs146554705

chr2-206791762-C-T

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.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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.261

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=0.0029308498).
• 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: {Uncertain_significance=1, Benign=1, Likely_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 GnomAd at 2 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152172 Hom.: 2 Cov.: 32

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.: 1 AF XY: 0.000531 AC XY: 72 AN XY: 135618

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.: 2 Cov.: 29 AF XY: 0.000239 AC XY: 174 AN XY: 726654

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.: 2 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74478

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.: 0

Bravo AF: 0.00267

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000914 AC: 111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

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	Invitae	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	T
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	N
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
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	T
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

Other links and lift over

dbSNP: rs146554705; hg19: chr2-207656486;