NM_003001.5:c.20+11_20+12dupTG

Variant names:

• chr1-161314434-A-AGT
• rs35215598
• NM_003001.5:c.20+11_20+12dupTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003001.5(SDHC):​c.20+11_20+12dupTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0822 in 1,613,892 control chromosomes in the GnomAD database, including 7,980 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1434 hom., cov: 30)
  • Exomes 𝑓: 0.078 (6546 hom.)
• Consequence: SDHC NM_003001.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.656

Genes affected

SDHC (HGNC:10682): (succinate dehydrogenase complex subunit C) This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-161314434-A-AGT is Benign according to our data. Variant chr1-161314434-A-AGT is described in ClinVar as [Benign]. Clinvar id is 44647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5	c.20+11_20+12dupTG		intron_variant	Intron 1 of 5	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.20+11_20+12dupTG		intron_variant	Intron 1 of 5	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17935 AN: 152046 Hom.: 1431 Cov.: 30

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0644

Gnomad OTH AF: 0.0946

GnomAD3 exomes AF: 0.0998 AC: 25060 AN: 251148 Hom.: 1737 AF XY: 0.100 AC XY: 13601 AN XY: 135768

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0784 AC: 114671 AN: 1461728 Hom.: 6546 Cov.: 30 AF XY: 0.0811 AC XY: 58942 AN XY: 727172

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.0539

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0964

Gnomad4 NFE exome AF: 0.0608

Gnomad4 OTH exome AF: 0.0820

GnomAD4 genome AF: 0.118 AC: 17957 AN: 152164 Hom.: 1434 Cov.: 30 AF XY: 0.121 AC XY: 8973 AN XY: 74378

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.209

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0644

Gnomad4 OTH AF: 0.0936

Alfa AF: 0.0810 Hom.: 166

Bravo AF: 0.116

Asia WGS AF: 0.202 AC: 699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SDHC c.20+11_20+12dupTG is an intronic variant at a position not widely known to affect splicing. One in silico tool (MutationTaster) predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant change to the normal splicing. This variant was found in 12727/120920 control chromosomes (including 891 homozygotes) at a frequency of 0.1052514, which is approximately 673609 times the estimated maximal expected allele frequency of a pathogenic SDHC variant (0.0000002), suggesting this variant is a common benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, based on the allele frequency in the general population, this variant is classified as Benign. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

20+11_20+12dupTG in intron 1 of SDHC: This variant has been identified in 15% ( 63/420) of patients with hereditary paraganglioma and in 6% (11/200) of controls (Burnichon 2009). This variant is also annotated as a common polymorphism in db SNP and but has been identified in 6% (516/8254) of European American chromosome s and 21% (889/4266) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs27118366). This variant i s located in the 5' splice region and computational tools do not suggest an impa ct to splicing. However, this information is not predictive enough to rule out p athogenicity. In summary, these data support that the 20+11_20+12dupTG variant i s benign based on frequency data. -

Charcot-Marie-Tooth disease type 4E Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Roussy-Lévy syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jul 08, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease, type I Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth, Intermediate Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs35215598; hg19: chr1-161284224;