chr11-61446034-C-T

Variant names:

• chr11-61446034-C-T
• rs1245083102
• NM_017841.4:c.464C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_017841.4(SDHAF2):​c.464C>T​(p.Ala155Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A155A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.96
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2879515).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.464C>T	p.Ala155Val	missense	Exon 4 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.464C>T	p.Ala155Val	missense	Exon 4 of 4	ENSP00000301761.3	Q9NX18
	ENSG00000256591	ENST00000541135.5	TSL:4	c.377+7914C>T		intron	N/A	ENSP00000443130.1	F5H5T6
	SDHAF2	ENST00000713963.1		c.557C>T	p.Ala186Val	missense	Exon 5 of 5	ENSP00000519256.1	A0AAQ5BH90

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251464 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary pheochromocytoma-paraganglioma (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.20		Gain of sheet (P = 0.1208)
MVP		0.75
MPC		0.61
ClinPred		0.90	D
GERP RS		4.5
Varity_R		0.29
gMVP		0.54
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: rs1245083102; hg19: chr11-61213506;