chr2-206765369-C-A

Position:

• chr2-206765369-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000236980.10(FASTKD2):​c.-336C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,505,988 control chromosomes in the GnomAD database, including 6,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1492 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5416 hom.)
• Consequence: FASTKD2 ENST00000236980.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.851

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]

MDH1B (HGNC:17836): (malate dehydrogenase 1B) Predicted to enable L-malate dehydrogenase activity. Predicted to be involved in NADH metabolic process; dicarboxylic acid metabolic process; and tricarboxylic acid cycle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-206765369-C-A is Benign according to our data. Variant chr2-206765369-C-A is described in ClinVar as [Benign]. Clinvar id is 1253085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDH1B	NM_001039845.3			upstream_gene_variant		ENST00000374412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD2	ENST00000236980.10	c.-336C>A		5_prime_UTR_variant	1/12	1		P1
FASTKD2	ENST00000418289.1	c.-200C>A		5_prime_UTR_variant	1/2	3
MDH1B	ENST00000374412.8			upstream_gene_variant		1	NM_001039845.3	P4
MDH1B	ENST00000449792.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17915 AN: 152066 Hom.: 1485 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.0881

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0835 AC: 113100 AN: 1353804 Hom.: 5416 Cov.: 31 AF XY: 0.0830 AC XY: 55274 AN XY: 665778

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.0513

Gnomad4 ASJ exome AF: 0.0415

Gnomad4 EAS exome AF: 0.0440

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0826

Gnomad4 OTH exome AF: 0.0883

GnomAD4 genome AF: 0.118 AC: 17949 AN: 152184 Hom.: 1492 Cov.: 32 AF XY: 0.115 AC XY: 8549 AN XY: 74400

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.0747

Gnomad4 ASJ AF: 0.0381

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.0883

Gnomad4 FIN AF: 0.0508

Gnomad4 NFE AF: 0.0774

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0843 Hom.: 1026

Bravo AF: 0.125

Asia WGS AF: 0.0810 AC: 285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.3
DANN	Benign	0.76

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: rs16838839; hg19: chr2-207630093;