chr11-61437651-A-G

Variant names:

• chr11-61437651-A-G
• rs191513932
• NM_017841.4:c.63A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017841.4(SDHAF2):​c.63A>G​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,614,168 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: SDHAF2 NM_017841.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.19
• Publications: 3 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, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000256591 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-61437651-A-G is Benign according to our data. Variant chr11-61437651-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000341 (52/152306) while in subpopulation EAS AF = 0.0081 (42/5186). AF 95% confidence interval is 0.00616. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 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.63A>G	p.Leu21Leu	synonymous	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.63A>G	p.Leu21Leu	synonymous	Exon 2 of 4	ENSP00000301761.3	Q9NX18
	ENSG00000256591	ENST00000541135.5	TSL:4	c.63A>G	p.Leu21Leu	synonymous	Exon 2 of 5	ENSP00000443130.1	F5H5T6
	SDHAF2	ENST00000713963.1		c.156A>G	p.Leu52Leu	synonymous	Exon 3 of 5	ENSP00000519256.1	A0AAQ5BH90

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000477 AC: 120 AN: 251470 AF XY: 0.000441

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.000326 AC XY: 237 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

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

East Asian (EAS) AF: 0.0109 AC: 432 AN: 39698

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111984

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74476

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000393

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary pheochromocytoma-paraganglioma (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs191513932; hg19: chr11-61205123;