1-161314434-AGT-AGTGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

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

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.656

Publications

2 publications found

Variant links:

COSMIC-nc: COSV60668638

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]

SDHC Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
pheochromocytoma/paraganglioma syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Carney-Stratakis syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
gastrointestinal stromal tumor
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial disease
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

SDHC links:

ENSG00000297068 (HGNC:):

ENSG00000297068 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 link	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 link	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.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0998

AC:

25060

AN:

251148

AF XY:

0.100

show subpopulations

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 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.:

AF XY:

0.0811

AC XY:

58942

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.224

AC:

7491

AN:

33472

American (AMR)

AF:

0.0539

AC:

2411

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

783

AN:

26132

East Asian (EAS)

AF:

0.260

AC:

10314

AN:

39692

South Asian (SAS)

AF:

0.181

AC:

15644

AN:

86258

European-Finnish (FIN)

AF:

0.0964

AC:

5148

AN:

53402

Middle Eastern (MID)

AF:

0.0578

AC:

333

AN:

5764

European-Non Finnish (NFE)

AF:

0.0608

AC:

67594

AN:

1111912

Other (OTH)

AF:

0.0820

AC:

4953

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5242

10484

15725

20967

26209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2706

5412

8118

10824

13530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.118

AC:

17957

AN:

152164

Hom.:

1434

Cov.:

AF XY:

0.121

AC XY:

8973

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.219

AC:

9080

AN:

41498

American (AMR)

AF:

0.0701

AC:

1072

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3470

East Asian (EAS)

AF:

0.209

AC:

1075

AN:

5150

South Asian (SAS)

AF:

0.187

AC:

901

AN:

4820

European-Finnish (FIN)

AF:

0.104

AC:

1104

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0644

AC:

4380

AN:

68012

Other (OTH)

AF:

0.0936

AC:

198

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

756

1512

2269

3025

3781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

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

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.

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over