chr2-206786740-G-T

Variant names:

• chr2-206786740-G-T
• rs145043229
• NM_001136193.2:c.1435G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001136193.2(FASTKD2):​c.1435G>T​(p.Val479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,613,734 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: FASTKD2 NM_001136193.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

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

ENSG00000299634 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005548626).
• BP6: Variant 2-206786740-G-T is Benign according to our data. Variant chr2-206786740-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377003.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (336/152258) while in subpopulation AFR AF = 0.00746 (310/41552). AF 95% confidence interval is 0.00678. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD2	NM_001136193.2	MANE Select	c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	NP_001129665.1	Q9NYY8-1
	FASTKD2	NM_001136194.2		c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	NP_001129666.1	Q9NYY8-1
	FASTKD2	NM_014929.4		c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	NP_055744.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD2	ENST00000402774.8	TSL:1 MANE Select	c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	ENSP00000385990.3	Q9NYY8-1
	FASTKD2	ENST00000236980.10	TSL:1	c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	ENSP00000236980.6	Q9NYY8-1
	FASTKD2	ENST00000403094.3	TSL:5	c.1435G>T	p.Val479Leu	missense	Exon 8 of 12	ENSP00000384929.3	Q9NYY8-1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 334 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.00240

GnomAD2 exomes AF: 0.000573 AC: 144 AN: 251394 AF XY: 0.000427

Gnomad AFR exome AF: 0.00726

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 727042

African (AFR) AF: 0.00762 AC: 255 AN: 33456

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111684

Other (OTH) AF: 0.000828 AC: 50 AN: 60382

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74456

African (AFR) AF: 0.00746 AC: 310 AN: 41552

American (AMR) AF: 0.00118 AC: 18 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00256

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.9	N
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.58		Loss of methylation at K475 (P = 0.0685)
MVP		0.12
MPC		0.16
ClinPred		0.0028	T
GERP RS		4.2
Varity_R		0.021
gMVP		0.11
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs145043229; hg19: chr2-207651464; COSMIC: COSV107249371; COSMIC: COSV107249371;