1-17027878-GGAAGAAGAAGAA-GGAAGAA

Position:

• chr1-17027878-GGAAGAAGAAGAA-GGAAGAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_003000.3(SDHB):​c.424-19_424-14delTTCTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,377,784 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 2.43

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 1-17027878-GGAAGAA-G is Benign according to our data. Variant chr1-17027878-GGAAGAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=4}. Variant chr1-17027878-GGAAGAA-G is described in Lovd as [Likely_benign]. Variant chr1-17027878-GGAAGAA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00222 (337/151668) while in subpopulation AMR AF= 0.00382 (58/15188). AF 95% confidence interval is 0.00303. There are 0 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.424-19_424-14delTTCTTC		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.370-19_370-14delTTCTTC		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.424-19_424-14delTTCTTC		intron_variant		1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 151552 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00382

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000574

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00224 AC: 500 AN: 222768 Hom.: 2 AF XY: 0.00238 AC XY: 287 AN XY: 120738

Gnomad AFR exome AF: 0.000978

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00433

Gnomad EAS exome AF: 0.000440

Gnomad SAS exome AF: 0.00230

Gnomad FIN exome AF: 0.000444

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00229 AC: 2813 AN: 1226116 Hom.: 11 AF XY: 0.00238 AC XY: 1483 AN XY: 622084

Gnomad4 AFR exome AF: 0.000795

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.00488

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.000538

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00324

GnomAD4 genome AF: 0.00222 AC: 337 AN: 151668 Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 160 AN XY: 74086

Gnomad4 AFR AF: 0.000556

Gnomad4 AMR AF: 0.00382

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.000574

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00427

Bravo AF: 0.00232

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Pheochromocytoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Carney-Stratakis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Paragangliomas 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34261028; hg19: chr1-17354373;