chr1-17027802-A-G

Position:

• chr1-17027802-A-G

Variant summary

Our verdict is Benign. Variant got -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).

• 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:24 O:1
• Conservation: PhyloP100: 4.71

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a region_of_interest Interaction with SDHAF1 (size 72) in uniprot entity SDHB_HUMAN there are 30 pathogenic changes around while only 1 benign (97%) 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 id is 12792.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=16, Uncertain_significance=3}. Variant chr1-17027802-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.487T>C	p.Ser163Pro	missense_variant	5/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.433T>C	p.Ser145Pro	missense_variant	5/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.487T>C	p.Ser163Pro	missense_variant	5/8	1	NM_003000.3	ENSP00000364649	P1

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

GnomAD3 exomes AF: 0.0121 AC: 3045 AN: 251388 Hom.: 33 AF XY: 0.0130 AC XY: 1760 AN XY: 135866

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 SAS exome AF: 0.0181

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

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0174

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0111

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

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0128 Hom.: 23

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:24 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:10 Other:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2017	Variant summary: The SDHB c.487T>C (p.Ser163Pro) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1523/121404 control chromosomes (21 homozygotes) at a frequency of 0.0125449, which largely exceeds the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Paragangliomas 4 Uncertain:2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -

not provided Uncertain:1 Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SDHB: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2018	This variant is associated with the following publications: (PMID: 19215943, 16322339, 17298551, 16912137, 22995991, 19768395, 22584711, 19802898, 19399650, 22293219, 24735130, 20981092, 27153395, 18678321, 21979946, 25376524, 22938532, 22703879, 25694510, 23666964, 25333069, 24728327, 26071763, 17102082, 17102083, 22270996, 25695889, 17639058, 14985401, 26182300, 18419787, 19153209, 19522823, 19454582, 27279923, 27884173, 26092435, 28374168, 29386252, 30050099, 31019283) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cowden syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Gastrointestinal stromal tumor Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Carney-Stratakis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0081	T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.47	N;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.44	N;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.77	T;.;.
Sift4G	Benign	1.0	T;T;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

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

Publications

LitVar

Other links and lift over

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