rs10887990

Variant names:

• chr1-17032891-T-C
• rs10887990
• NM_003000.3:c.286+169A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-17032891-T-C
• chr1-17032891-T-G

Variant summary

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

The ENST00000375499.8(SDHB):​c.286+169A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 677,548 control chromosomes in the GnomAD database, including 81,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15162 hom., cov: 32)
  • Exomes 𝑓: 0.50 (66403 hom.)
• Consequence: SDHB ENST00000375499.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69
• Publications: 13 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: Genomics England PanelApp, Ambry Genetics, 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=-0.65).
• BP6: Variant 1-17032891-T-C is Benign according to our data. Variant chr1-17032891-T-C is described in ClinVar as Benign. ClinVar VariationId is 1234802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375499.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.286+169A>G		intron	N/A	NP_002991.2
	SDHB	NM_001407361.1		c.286+169A>G		intron	N/A	NP_001394290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.286+169A>G		intron	N/A	ENSP00000364649.3
	SDHB	ENST00000466613.2	TSL:2	n.467A>G		non_coding_transcript_exon	Exon 3 of 3
	SDHB	ENST00000714034.1		c.331+169A>G		intron	N/A	ENSP00000519325.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64082 AN: 151968 Hom.: 15159 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.495 AC: 260231 AN: 525460 Hom.: 66403 Cov.: 4 AF XY: 0.495 AC XY: 139967 AN XY: 282562

African (AFR) AF: 0.195 AC: 2751 AN: 14100

American (AMR) AF: 0.485 AC: 13781 AN: 28428

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 8356 AN: 17476

East Asian (EAS) AF: 0.315 AC: 9931 AN: 31502

South Asian (SAS) AF: 0.460 AC: 25861 AN: 56184

European-Finnish (FIN) AF: 0.505 AC: 23130 AN: 45796

Middle Eastern (MID) AF: 0.494 AC: 1378 AN: 2788

European-Non Finnish (NFE) AF: 0.537 AC: 161554 AN: 300616

Other (OTH) AF: 0.472 AC: 13489 AN: 28570

GnomAD4 genome AF: 0.421 AC: 64087 AN: 152088 Hom.: 15162 Cov.: 32 AF XY: 0.418 AC XY: 31089 AN XY: 74338

African (AFR) AF: 0.198 AC: 8212 AN: 41520

American (AMR) AF: 0.455 AC: 6956 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1595 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1551 AN: 5166

South Asian (SAS) AF: 0.449 AC: 2163 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5179 AN: 10550

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36828 AN: 67968

Other (OTH) AF: 0.438 AC: 927 AN: 2116

Alfa AF: 0.491 Hom.: 23378

Bravo AF: 0.410

Asia WGS AF: 0.355 AC: 1238 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.4
DANN	Benign	0.85
PhyloP100		-1.7
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: rs10887990; hg19: chr1-17359386;