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).

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.43G>C	p.Ala15Pro	missense	Exon 2 of 4	NP_060311.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF2	ENST00000301761.7	TSL:1 MANE Select	c.43G>C	p.Ala15Pro	missense	Exon 2 of 4	ENSP00000301761.3
	ENSG00000256591	ENST00000541135.5	TSL:4	c.43G>C	p.Ala15Pro	missense	Exon 2 of 5	ENSP00000443130.1
	SDHAF2	ENST00000713963.1		c.136G>C	p.Ala46Pro	missense	Exon 3 of 5	ENSP00000519256.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.56
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.029	D
Sift4G	Benign	0.070	T
Polyphen		0.61	P
Vest4		0.21
MutPred		0.27		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;