chr1-17023748-T-C

Variant names:

• chr1-17023748-T-C
• rs2647162
• NM_003000.3:c.642+225A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003000.3(SDHB):​c.642+225A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,214 control chromosomes in the GnomAD database, including 7,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (7190 hom., cov: 33)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.10
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-17023748-T-C is Benign according to our data. Variant chr1-17023748-T-C is described in ClinVar as Benign. ClinVar VariationId is 1269910.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.642+225A>G		intron_variant	Intron 6 of 7	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.588+225A>G		intron_variant	Intron 6 of 7		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.642+225A>G		intron_variant	Intron 6 of 7	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39837 AN: 152096 Hom.: 7169 Cov.: 33

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.0667

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.262 AC: 39898 AN: 152214 Hom.: 7190 Cov.: 33 AF XY: 0.256 AC XY: 19088 AN XY: 74432

African (AFR) AF: 0.515 AC: 21372 AN: 41502

American (AMR) AF: 0.165 AC: 2526 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 796 AN: 3472

East Asian (EAS) AF: 0.0661 AC: 343 AN: 5190

South Asian (SAS) AF: 0.110 AC: 533 AN: 4830

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10602

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11982 AN: 68010

Other (OTH) AF: 0.219 AC: 462 AN: 2110

Alfa AF: 0.229 Hom.: 660

Bravo AF: 0.272

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.46
DANN	Benign	0.33
PhyloP100		-2.1
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: rs2647162; hg19: chr1-17350243; COSMIC: COSV64964961; COSMIC: COSV64964961;