rs182629842

chr1-161362511-G-Achr1-161362511-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000342751.8(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 ENST00000342751.8 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:6
• Conservation: PhyloP100: 1.95

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 -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. This position pass quality control queck.
• BS2: High AC in GnomAd at 268 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHC	NM_003001.5	c.*78G>A		3_prime_UTR_variant	6/6	ENST00000367975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHC	ENST00000367975.7	c.*78G>A		3_prime_UTR_variant	6/6	1	NM_003001.5	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 151970 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.00175 AC XY: 226 AN XY: 129264

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.: 4 Cov.: 35 AF XY: 0.00207 AC XY: 1502 AN XY: 725248

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.: 0 Cov.: 31 AF XY: 0.00172 AC XY: 128 AN XY: 74366

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.: 0

Bravo AF: 0.00164

ESP6500AA AF: 0.000462 AC: 2

ESP6500EA AF: 0.00235 AC: 20

ExAC AF: 0.00167 AC: 202

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SDHC: PP3, BS1 -
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) -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary pheochromocytoma-paraganglioma Uncertain:1 Benign:1

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. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -

SDHC-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	N;N;N
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	T
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

Other links and lift over

dbSNP: rs182629842; hg19: chr1-161332301;