2-206769512-T-G

Variant names:

• chr2-206769512-T-G
• rs2277912
• NM_001136193.2:c.778-579T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001136193.2(FASTKD2):​c.778-579T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,196 control chromosomes in the GnomAD database, including 1,604 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1604 hom., cov: 32)
• Consequence: FASTKD2 NM_001136193.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD2	NM_001136193.2	c.778-579T>G		intron_variant	Intron 2 of 11	ENST00000402774.8	NP_001129665.1
FASTKD2	NM_001136194.2	c.778-579T>G		intron_variant	Intron 2 of 11		NP_001129666.1
FASTKD2	NM_014929.4	c.778-579T>G		intron_variant	Intron 2 of 11		NP_055744.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASTKD2	ENST00000402774.8	c.778-579T>G		intron_variant	Intron 2 of 11	1	NM_001136193.2	ENSP00000385990.3
FASTKD2	ENST00000236980.10	c.778-579T>G		intron_variant	Intron 2 of 11	1		ENSP00000236980.6
FASTKD2	ENST00000403094.3	c.778-579T>G		intron_variant	Intron 2 of 11	5		ENSP00000384929.3
FASTKD2	ENST00000487777.5	n.836-579T>G		intron_variant	Intron 2 of 9	5

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19272 AN: 152078 Hom.: 1599 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.127 AC: 19288 AN: 152196 Hom.: 1604 Cov.: 32 AF XY: 0.126 AC XY: 9399 AN XY: 74396

African (AFR) AF: 0.0309 AC: 1283 AN: 41540

American (AMR) AF: 0.109 AC: 1663 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3472

East Asian (EAS) AF: 0.152 AC: 788 AN: 5174

South Asian (SAS) AF: 0.202 AC: 976 AN: 4826

European-Finnish (FIN) AF: 0.146 AC: 1547 AN: 10594

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11818 AN: 67982

Other (OTH) AF: 0.122 AC: 258 AN: 2108

Alfa AF: 0.155 Hom.: 7153

Bravo AF: 0.118

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.95
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2277912; hg19: chr2-207634236;