rs182629842

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035511.3(SDHC):c.424G>A(p.Ala142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,610,112 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

SDHC
NM_001035511.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:2B:7

Conservation

PhyloP100: 1.95

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:

SDHC (HGNC:):

SDHC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072749257).

BP6

Variant 1-161362511-G-A is Benign according to our data. Variant chr1-161362511-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161362511-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00176 (267/152088) while in subpopulation AMR AF= 0.00281 (43/15282). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.*78G>A		3_prime_UTR_variant	6/6	ENST00000367975.7	NP_002992.1	Q99643-1A0A0S2Z4B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 linkuse as main transcript	c.*78G>A		3_prime_UTR_variant	6/6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00169

AC:

403

AN:

237948

Hom.:

AF XY:

0.00175

AC XY:

226

AN XY:

129264

show subpopulations

Gnomad AFR exome

AF:

0.000265

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00264

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000537

Gnomad FIN exome

AF:

0.00123

Gnomad NFE exome

AF:

0.00257

Gnomad OTH exome

AF:

0.00307

GnomAD4 exome

AF:

0.00214

AC:

3122

AN:

1458024

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1502

AN XY:

725248

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.00144

Gnomad4 ASJ exome

AF:

0.00318

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000547

Gnomad4 FIN exome

AF:

0.00113

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

152088

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000579

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00257

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.000462

AC:

ESP6500EA

AF:

0.00235

AC:

ExAC

AF:

0.00167

AC:

202

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SDHC: PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	This variant is associated with the following publications: (PMID: 26073078, 22703879, 25352556) -

Hereditary pheochromocytoma-paraganglioma

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 22, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

SDHC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

5.3

DANN

Benign

0.53

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.0073

T;T

MetaSVM

Uncertain

-0.23

PROVEAN

Benign

0.12

N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.30

T;T

Polyphen

0.0

B;B

Vest4

0.20

MVP

0.80

ClinPred

0.025

GERP RS

1.8

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