chr1-17033181-C-A

Variant names:

• chr1-17033181-C-A
• rs1022580
• NM_003000.3:c.201-36G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003000.3(SDHB):​c.201-36G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,503,420 control chromosomes in the GnomAD database, including 710,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69693 hom., cov: 32)
  • Exomes 𝑓: 0.97 (640992 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.294
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-17033181-C-A is Benign according to our data. Variant chr1-17033181-C-A is described in ClinVar as Benign. ClinVar VariationId is 258889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

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.201-36G>T		intron	N/A	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.201-36G>T		intron	N/A	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.201-36G>T		intron	N/A	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.246-36G>T		intron	N/A	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.201-36G>T		intron	N/A	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145515 AN: 152160 Hom.: 69638 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.953

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.973

Gnomad OTH AF: 0.950

GnomAD2 exomes AF: 0.973 AC: 241645 AN: 248256 AF XY: 0.974

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.974 AC: 1315992 AN: 1351142 Hom.: 640992 Cov.: 19 AF XY: 0.974 AC XY: 660815 AN XY: 678160

African (AFR) AF: 0.913 AC: 28424 AN: 31122

American (AMR) AF: 0.981 AC: 43557 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 24156 AN: 25312

East Asian (EAS) AF: 0.987 AC: 38687 AN: 39182

South Asian (SAS) AF: 0.988 AC: 82707 AN: 83708

European-Finnish (FIN) AF: 0.979 AC: 52176 AN: 53316

Middle Eastern (MID) AF: 0.963 AC: 5291 AN: 5494

European-Non Finnish (NFE) AF: 0.974 AC: 985985 AN: 1011962

Other (OTH) AF: 0.971 AC: 55009 AN: 56656

GnomAD4 genome AF: 0.956 AC: 145628 AN: 152278 Hom.: 69693 Cov.: 32 AF XY: 0.958 AC XY: 71307 AN XY: 74458

African (AFR) AF: 0.910 AC: 37789 AN: 41540

American (AMR) AF: 0.971 AC: 14849 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 3305 AN: 3468

East Asian (EAS) AF: 0.995 AC: 5153 AN: 5178

South Asian (SAS) AF: 0.991 AC: 4787 AN: 4830

European-Finnish (FIN) AF: 0.979 AC: 10401 AN: 10624

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.973 AC: 66197 AN: 68020

Other (OTH) AF: 0.951 AC: 2010 AN: 2114

Alfa AF: 0.964 Hom.: 102923

Bravo AF: 0.953

Asia WGS AF: 0.986 AC: 3430 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Pheochromocytoma/paraganglioma syndrome 4 (2)
-	-	1	Gastrointestinal stromal tumor (1)
-	-	1	Mitochondrial complex 2 deficiency, nuclear type 4 (1)
-	-	1	not specified (1)
-	-	1	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.65
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs1022580; hg19: chr1-17359676;