rs772219112

Variant names:

• chr11-61446014-CAA-C
• rs772219112
• NM_017841.4:c.446_447delAA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_017841.4(SDHAF2):​c.446_447delAA​(p.Lys149ArgfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000157 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.96

Genes affected

SDHAF2 (HGNC:26034): (succinate dehydrogenase complex assembly factor 2) This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

ENSG00000256591 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.11 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.446_447delAA	p.Lys149ArgfsTer10	frameshift_variant	Exon 4 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.446_447delAA	p.Lys149ArgfsTer10	frameshift_variant	Exon 4 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.377+7896_377+7897delAA		intron_variant	Intron 3 of 4	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251476 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461870 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 18 amino acids are replaced with 9 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with congenital heart disease (PMID: 33084842); This variant is associated with the following publications: (PMID: 33084842) -

Jul 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pheochromocytoma-paraganglioma Uncertain:2

May 04, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 4 of the SDHAF2 gene, creating a frameshift and a premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, impacting the last 18 amino acids of SDHAF2. To our knowledge, experimental functional studies have not been reported for this variant, and it has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has been identified in 2/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys149Argfs*10) in the SDHAF2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the SDHAF2 protein. This variant is present in population databases (rs772219112, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 403424). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Mar 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Lys149Argfs variant in SDHAF2 has not been previously reported, but has been identified in 1/66724 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant is expected to severely impact the protein, the spectrum of disease-causing variants is not well defined for SDHAF2. In summary, the clinical significance of the p.Lys149Argfs variant is uncertain. -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446_447delAA variant, located in coding exon 4 of the SDHAF2 gene, results from a deletion of two nucleotides at nucleotide positions 446 to 447, causing a translational frameshift with a predicted alternate stop codon (p.K149Rfs*10). This alteration occurs at the 3' terminus of SDHAF2, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 10.8% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

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: rs772219112; hg19: chr11-61213486;