ENST00000342751.8:c.430G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000342751.8(SDHC):c.430G>C(p.Glu144Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,609,238 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 10 hom., cov: 31)

Exomes 𝑓: 0.011 ( 80 hom. )

Consequence

SDHC
ENST00000342751.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11O:1

Conservation

PhyloP100: -0.389

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006989956).

BP6

Variant 1-161362517-G-C is Benign according to our data. Variant chr1-161362517-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41773.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=8, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00681 (1037/152178) while in subpopulation NFE AF= 0.0119 (806/68012). AF 95% confidence interval is 0.0112. There are 10 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1037 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.*84G>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000367975.7	NP_002992.1	Q99643-1A0A0S2Z4B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 link	c.*84G>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00682

AC:

1037

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00536

AC:

1268

AN:

236416

Hom.:

AF XY:

0.00518

AC XY:

666

AN XY:

128462

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00992

Gnomad OTH exome

AF:

0.00741

GnomAD4 exome

AF:

0.0114

AC:

16674

AN:

1457060

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

8073

AN XY:

724684

show subpopulations

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.00269

Gnomad4 ASJ exome

AF:

0.00495

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00240

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00681

AC:

1037

AN:

152178

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

451

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00251

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00754

Hom.:

Bravo

AF:

0.00713

ESP6500AA

AF:

0.00187

AC:

ESP6500EA

AF:

0.00813

AC:

ExAC

AF:

0.00489

AC:

592

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHC: PP3, BS1, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28220018, 24728327) -

Oct 29, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma

Benign:1

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 3

Benign:1

Feb 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

1.1

DANN

Uncertain

0.98

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.52

T;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.0070

T;T

MetaSVM

Uncertain

-0.20

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.10

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.26

B;B

Vest4

0.16

MVP

0.81

ClinPred

0.0048

GERP RS

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over