chr11-61438074-G-C

Variant names:

• chr11-61438074-G-C
• rs145616631
• NM_017841.4:c.331G>C

Variant summary

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

The NM_017841.4(SDHAF2):​c.331G>C​(p.Glu111Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E111K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.331G>C	p.Glu111Gln	missense	Exon 3 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.331G>C	p.Glu111Gln	missense	Exon 3 of 4	ENSP00000301761.3	Q9NX18
	ENSG00000256591	ENST00000541135.5	TSL:4	c.331G>C	p.Glu111Gln	missense	Exon 3 of 5	ENSP00000443130.1	F5H5T6
	SDHAF2	ENST00000713963.1		c.424G>C	p.Glu142Gln	missense	Exon 4 of 5	ENSP00000519256.1	A0AAQ5BH90

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary pheochromocytoma and paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.43
Sift	Benign	0.051	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.59		Loss of catalytic residue at E111 (P = 0.1089)
MVP		0.75
MPC		0.51
ClinPred		0.83	D
GERP RS		6.2
Varity_R		0.36
gMVP		0.63
Mutation Taster		=55/45	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: rs145616631; hg19: chr11-61205546;