rs116297724

Variant names:

• chr2-206765747-A-G
• rs116297724
• NM_001136193.2:c.-51A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001136193.2(FASTKD2):​c.-51A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 159,928 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (11 hom., cov: 31)
  • Exomes 𝑓: 0.014 (2 hom.)
• Consequence: FASTKD2 NM_001136193.2 splice_region
• Scores: Splicing: ADA: 0.0004047
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.16
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-206765747-A-G is Benign according to our data. Variant chr2-206765747-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0089 (1355/152220) while in subpopulation NFE AF = 0.0125 (849/68020). AF 95% confidence interval is 0.0118. There are 11 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.-51A>G		splice_region	Exon 1 of 12	NP_001129665.1
	FASTKD2	NM_001136193.2	MANE Select	c.-51A>G		5_prime_UTR	Exon 1 of 12	NP_001129665.1
	FASTKD2	NM_001136194.2		c.-66A>G		5_prime_UTR	Exon 1 of 12	NP_001129666.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD2	ENST00000402774.8	TSL:1 MANE Select	c.-51A>G		splice_region	Exon 1 of 12	ENSP00000385990.3
	FASTKD2	ENST00000402774.8	TSL:1 MANE Select	c.-51A>G		5_prime_UTR	Exon 1 of 12	ENSP00000385990.3
	FASTKD2	ENST00000236980.10	TSL:1	c.-51+93A>G		intron	N/A	ENSP00000236980.6

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152102 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.0139 AC: 107 AN: 7708 Hom.: 2 Cov.: 4 AF XY: 0.0139 AC XY: 54 AN XY: 3876

African (AFR) AF: 0.00 AC: 0 AN: 176

American (AMR) AF: 0.00 AC: 0 AN: 30

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 82

East Asian (EAS) AF: 0.00 AC: 0 AN: 46

South Asian (SAS) AF: 0.00 AC: 0 AN: 348

European-Finnish (FIN) AF: 0.0200 AC: 1 AN: 50

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.0154 AC: 103 AN: 6672

Other (OTH) AF: 0.0106 AC: 3 AN: 284

GnomAD4 genome AF: 0.00890 AC: 1355 AN: 152220 Hom.: 11 Cov.: 31 AF XY: 0.00981 AC XY: 730 AN XY: 74420

African (AFR) AF: 0.00156 AC: 65 AN: 41542

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0335 AC: 355 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0125 AC: 849 AN: 68020

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.0115 Hom.: 2

Bravo AF: 0.00631

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Combined oxidative phosphorylation deficiency 44 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-1.2
PromoterAI		-0.056	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.15		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: rs116297724; hg19: chr2-207630471;