rs752462796

Variant names:

• chr11-61437782-C-G
• rs752462796
• NM_017841.4:c.194C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-61437782-C-G
• chr11-61437782-C-T
• chr11-61437782-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_017841.4(SDHAF2):​c.194C>G​(p.Thr65Ser) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T65I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.38
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.2651273).
• BP6: Variant 11-61437782-C-G is Benign according to our data. Variant chr11-61437782-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1488680.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017841.4. 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
	SDHAF2	NM_017841.4	MANE Select	c.194C>G	p.Thr65Ser	missense	Exon 2 of 4	NP_060311.1	Q9NX18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF2	ENST00000301761.7	TSL:1 MANE Select	c.194C>G	p.Thr65Ser	missense	Exon 2 of 4	ENSP00000301761.3	Q9NX18
	ENSG00000256591	ENST00000541135.5	TSL:4	c.194C>G	p.Thr65Ser	missense	Exon 2 of 5	ENSP00000443130.1	F5H5T6
	SDHAF2	ENST00000713963.1		c.287C>G	p.Thr96Ser	missense	Exon 3 of 5	ENSP00000519256.1	A0AAQ5BH90

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.057	T
Sift4G	Benign	0.074	T
Polyphen		0.31	B
Vest4		0.41
MutPred		0.22		Gain of disorder (P = 0.0789)
MVP		0.49
MPC		0.17
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.30
Mutation Taster		=82/18	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: rs752462796; hg19: chr11-61205254;