rs2235930

Variant names:

• chr1-17023648-G-A
• rs2235930
• NM_003000.3:c.642+325C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-17023648-G-A
• chr1-17023648-G-C

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.642+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 152,026 control chromosomes in the GnomAD database, including 21,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.51 (21272 hom., cov: 32)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.252
• Publications: 4 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=-0.88).
• BP6: Variant 1-17023648-G-A is Benign according to our data. Variant chr1-17023648-G-A is described in ClinVar as Benign. ClinVar VariationId is 695745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 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.642+325C>T		intron	N/A	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.588+325C>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.642+325C>T		intron	N/A	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.687+325C>T		intron	N/A	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.636+325C>T		intron	N/A	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77750 AN: 151910 Hom.: 21225 Cov.: 32

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.481

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77851 AN: 152026 Hom.: 21272 Cov.: 32 AF XY: 0.517 AC XY: 38403 AN XY: 74288

African (AFR) AF: 0.698 AC: 28946 AN: 41448

American (AMR) AF: 0.497 AC: 7583 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1691 AN: 3470

East Asian (EAS) AF: 0.694 AC: 3582 AN: 5164

South Asian (SAS) AF: 0.519 AC: 2503 AN: 4822

European-Finnish (FIN) AF: 0.448 AC: 4729 AN: 10552

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27425 AN: 67982

Other (OTH) AF: 0.487 AC: 1029 AN: 2112

Alfa AF: 0.454 Hom.: 1975

Bravo AF: 0.522

Asia WGS AF: 0.622 AC: 2163 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.61
PhyloP100		0.25
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: rs2235930; hg19: chr1-17350143; COSMIC: COSV64964957; COSMIC: COSV64964957;