rs148738139

Variant names:

• chr1-17053996-G-A
• rs148738139
• NM_003000.3:c.24C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-17053996-G-A
• chr1-17053996-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003000.3(SDHB):​c.24C>T​(p.Ser8Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00554 in 1,612,708 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: SDHB NM_003000.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 3.70
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-17053996-G-A is Benign according to our data. Variant chr1-17053996-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 184192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00437 (665/152316) while in subpopulation NFE AF = 0.00657 (447/68032). AF 95% confidence interval is 0.00607. There are 2 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.24C>T	p.Ser8Ser	synonymous	Exon 1 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.24C>T	p.Ser8Ser	synonymous	Exon 1 of 8	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.24C>T	p.Ser8Ser	synonymous	Exon 1 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.24C>T	p.Ser8Ser	synonymous	Exon 1 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.24C>T	p.Ser8Ser	synonymous	Exon 1 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152198 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00430 AC: 1043 AN: 242730 AF XY: 0.00418

Gnomad AFR exome AF: 0.000980

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00566 AC: 8269 AN: 1460392 Hom.: 29 Cov.: 30 AF XY: 0.00552 AC XY: 4012 AN XY: 726450

African (AFR) AF: 0.000747 AC: 25 AN: 33448

American (AMR) AF: 0.000358 AC: 16 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86050

European-Finnish (FIN) AF: 0.0144 AC: 761 AN: 53024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00646 AC: 7176 AN: 1111504

Other (OTH) AF: 0.00392 AC: 236 AN: 60244

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152316 Hom.: 2 Cov.: 31 AF XY: 0.00415 AC XY: 309 AN XY: 74466

African (AFR) AF: 0.000986 AC: 41 AN: 41578

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00491 Hom.: 2

Bravo AF: 0.00337

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00487

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	-	2	Hereditary pheochromocytoma-paraganglioma (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 4 (2)
-	-	1	Carney-Stratakis syndrome (1)
-	-	1	Gastrointestinal stromal tumor (1)
-	-	1	Hereditary cancer-predisposing syndrome (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	-0.46
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		3.7
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs148738139; hg19: chr1-17380491; COSMIC: COSV64965451;