1-17054002-G-T

Variant names:

• chr1-17054002-G-T
• rs2746462
• NM_003000.3:c.18C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003000.3(SDHB):​c.18C>A​(p.Ala6Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,611,714 control chromosomes in the GnomAD database, including 761,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (69641 hom., cov: 34)
  • Exomes 𝑓: 0.97 (692112 hom.)
• Consequence: SDHB NM_003000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -1.35
• Publications: 38 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-17054002-G-T is Benign according to our data. Variant chr1-17054002-G-T is described in ClinVar as Benign. ClinVar VariationId is 44641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

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.18C>A	p.Ala6Ala	synonymous	Exon 1 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.18C>A	p.Ala6Ala	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.18C>A	p.Ala6Ala	synonymous	Exon 1 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.18C>A	p.Ala6Ala	synonymous	Exon 1 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.18C>A	p.Ala6Ala	synonymous	Exon 1 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145453 AN: 152150 Hom.: 69588 Cov.: 34

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.953

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.974

Gnomad OTH AF: 0.952

GnomAD2 exomes AF: 0.974 AC: 235203 AN: 241566 AF XY: 0.975

Gnomad AFR exome AF: 0.913

Gnomad AMR exome AF: 0.983

Gnomad ASJ exome AF: 0.955

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.974 AC: 1421196 AN: 1459446 Hom.: 692112 Cov.: 43 AF XY: 0.974 AC XY: 707274 AN XY: 725928

African (AFR) AF: 0.910 AC: 30406 AN: 33416

American (AMR) AF: 0.982 AC: 43773 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 24887 AN: 26074

East Asian (EAS) AF: 0.988 AC: 39141 AN: 39634

South Asian (SAS) AF: 0.988 AC: 84865 AN: 85890

European-Finnish (FIN) AF: 0.979 AC: 51677 AN: 52810

Middle Eastern (MID) AF: 0.965 AC: 5484 AN: 5684

European-Non Finnish (NFE) AF: 0.974 AC: 1082491 AN: 1111154

Other (OTH) AF: 0.971 AC: 58472 AN: 60190

GnomAD4 genome AF: 0.956 AC: 145564 AN: 152268 Hom.: 69641 Cov.: 34 AF XY: 0.957 AC XY: 71261 AN XY: 74446

African (AFR) AF: 0.908 AC: 37714 AN: 41552

American (AMR) AF: 0.971 AC: 14852 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 3305 AN: 3468

East Asian (EAS) AF: 0.996 AC: 5143 AN: 5164

South Asian (SAS) AF: 0.991 AC: 4790 AN: 4832

European-Finnish (FIN) AF: 0.979 AC: 10392 AN: 10614

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.974 AC: 66214 AN: 68016

Other (OTH) AF: 0.952 AC: 2013 AN: 2114

Alfa AF: 0.965 Hom.: 49468

Bravo AF: 0.952

EpiCase AF: 0.973

EpiControl AF: 0.969

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	3	Pheochromocytoma/paraganglioma syndrome 4 (3)
-	-	2	Carney-Stratakis syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Hereditary pheochromocytoma-paraganglioma (2)
-	-	1	Gastrointestinal stromal tumor (1)
-	-	1	Mitochondrial complex 2 deficiency, nuclear type 4 (1)
-	-	1	Pheochromocytoma (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	-0.81
CADD	Benign	2.1
DANN	Benign	0.69
PhyloP100		-1.3
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2746462; hg19: chr1-17380497; COSMIC: COSV108226518; COSMIC: COSV108226518;