rs33927012

Variant names:

• chr1-17027802-A-G
• rs33927012
• NM_003000.3:c.487T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-17027802-A-G
• chr1-17027802-A-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_003000.3(SDHB):​c.487T>C​(p.Ser163Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0131 in 1,613,448 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts 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. S163F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0095 (14 hom., cov: 32)
  • Exomes 𝑓: 0.013 (193 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:27 O:1
• Conservation: PhyloP100: 4.71
• Publications: 52 publications found

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

SDHB Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a region_of_interest Interaction with SDHAF1 (size 72) in uniprot entity SDHB_HUMAN there are 37 pathogenic changes around while only 2 benign (95%) in NM_003000.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008068502).
• BP6: Variant 1-17027802-A-G is Benign according to our data. Variant chr1-17027802-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12792.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00947 (1441/152204) while in subpopulation SAS AF = 0.0193 (93/4824). AF 95% confidence interval is 0.0161. There are 14 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. 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
	SDHB	NM_003000.3	MANE Select	c.487T>C	p.Ser163Pro	missense	Exon 5 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.433T>C	p.Ser145Pro	missense	Exon 5 of 8	NP_001394290.1	A0AAQ5BHD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.487T>C	p.Ser163Pro	missense	Exon 5 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.532T>C	p.Ser178Pro	missense	Exon 6 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.481T>C	p.Ser161Pro	missense	Exon 5 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.00947 AC: 1441 AN: 152086 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.0121 AC: 3045 AN: 251388 AF XY: 0.0130

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0135 AC: 19718 AN: 1461244 Hom.: 193 Cov.: 29 AF XY: 0.0137 AC XY: 9927 AN XY: 726966

African (AFR) AF: 0.00215 AC: 72 AN: 33474

American (AMR) AF: 0.00362 AC: 162 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 160 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0174 AC: 1505 AN: 86248

European-Finnish (FIN) AF: 0.0215 AC: 1149 AN: 53366

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.0143 AC: 15925 AN: 1111470

Other (OTH) AF: 0.0111 AC: 673 AN: 60382

GnomAD4 genome AF: 0.00947 AC: 1441 AN: 152204 Hom.: 14 Cov.: 32 AF XY: 0.00963 AC XY: 717 AN XY: 74424

African (AFR) AF: 0.00178 AC: 74 AN: 41552

American (AMR) AF: 0.00465 AC: 71 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4824

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 960 AN: 67998

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.0121 Hom.: 54

Bravo AF: 0.00751

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.0125 AC: 1523

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0149

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (12)
-	1	4	not provided (5)
-	2	3	Pheochromocytoma/paraganglioma syndrome 4 (5)
-	-	2	Gastrointestinal stromal tumor (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Hereditary pheochromocytoma and paraganglioma (2)
-	-	1	Carney-Stratakis syndrome (1)
-	1	-	Cowden syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.47	N
PhyloP100		4.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.44	N
REVEL	Uncertain	0.44
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.21
ClinPred		0.025	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.76
Mutation Taster		=44/56	disease causing

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: rs33927012; hg19: chr1-17354297; COSMIC: COSV64965186; COSMIC: COSV64965186;