rs2647162

chr1-17023748-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	UniProt
SDHB	NM_003000.3	c.642+225A>G		intron_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.588+225A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.642+225A>G		intron_variant		1	NM_003000.3	P1
SDHB	ENST00000463045.3	c.471+225A>G		intron_variant		3
SDHB	ENST00000491274.6	c.600+225A>G		intron_variant		5
SDHB	ENST00000485515.5	n.576+225A>G		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR AF: 0.515

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.0661

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.219

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.46
Dann	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs2647162; hg19: chr1-17350243; COSMIC: COSV64964961; COSMIC: COSV64964961;