rs1002894711

Variant names:

• chr11-61437631-G-C
• rs1002894711
• NM_017841.4:c.43G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-61437631-G-C
• chr11-61437631-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017841.4(SDHAF2):​c.43G>C​(p.Ala15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.565
• Publications: 0 publications found

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]

SDHAF2 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma/paraganglioma syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000256591 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1479696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.43G>C	p.Ala15Pro	missense_variant	Exon 2 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.43G>C	p.Ala15Pro	missense_variant	Exon 2 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.43G>C	p.Ala15Pro	missense_variant	Exon 2 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A15P variant (also known as c.43G>C), located in coding exon 2 of the SDHAF2 gene, results from a G to C substitution at nucleotide position 43. The alanine at codon 15 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Oct 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with proline at codon 15 of the SDHAF2 protein (p.Ala15Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHAF2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	2.9
DANN	Benign	0.96
DEOGEN2	Benign	0.042	.;T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.54	T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	.;M;.;.;.
PhyloP100		-0.56
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;N;.;.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.029	D;T;.;.;T
Sift4G	Benign	0.070	T;T;T;T;T
Polyphen		0.61	.;P;.;.;.
Vest4		0.21, 0.27, 0.25, 0.34
MutPred		0.27		Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);Gain of loop (P = 0.002);
MVP		0.38
MPC		0.25
ClinPred		0.25	T
GERP RS		0.94
Varity_R		0.14
gMVP		0.42
Mutation Taster		=92/8	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: rs1002894711; hg19: chr11-61205103;