rs79652942

chr2-206772253-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001136193.2(FASTKD2):c.1187A>G(p.Asn396Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,613,872 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: FASTKD2 NM_001136193.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.74

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=0.004810989).
• BP6: Variant 2-206772253-A-G is Benign according to our data. Variant chr2-206772253-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 214348.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 = 0.00979 (1492/152356) while in subpopulation AFR AF= 0.0328 (1364/41578). AF 95% confidence interval is 0.0314. There are 26 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD2	NM_001136193.2	c.1187A>G	p.Asn396Ser	missense_variant	6/12	ENST00000402774.8
FASTKD2	NM_001136194.2	c.1187A>G	p.Asn396Ser	missense_variant	6/12
FASTKD2	NM_014929.4	c.1187A>G	p.Asn396Ser	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000402774.8	c.1187A>G	p.Asn396Ser	missense_variant	6/12	1	NM_001136193.2	P1
FASTKD2	ENST00000236980.10	c.1187A>G	p.Asn396Ser	missense_variant	6/12	1		P1
FASTKD2	ENST00000403094.3	c.1187A>G	p.Asn396Ser	missense_variant	6/12	5		P1
FASTKD2	ENST00000487777.5	n.1245A>G		non_coding_transcript_exon_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1485 AN: 152238 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

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: 0.000206

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00240 AC: 602 AN: 251338 Hom.: 4 AF XY: 0.00178 AC XY: 242 AN XY: 135846

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00102 AC: 1488 AN: 1461516 Hom.: 13 Cov.: 31 AF XY: 0.000915 AC XY: 665 AN XY: 727092

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00979 AC: 1492 AN: 152356 Hom.: 26 Cov.: 32 AF XY: 0.00935 AC XY: 697 AN XY: 74514

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00163 Hom.: 5

Bravo AF: 0.0108

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00309 AC: 375

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	2.9	M;M;M
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.66
MVP		0.41
MPC		0.61
ClinPred		0.052	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79652942; hg19: chr2-207636977; COSMIC: COSV99030949;