rs3813632

Positions:

• chr1-161362556-C-G
• chr1-161362556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003001.5(SDHC):​c.*123C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,607,096 control chromosomes in the GnomAD database, including 6,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (645 hom., cov: 31)
  • Exomes 𝑓: 0.075 (5509 hom.)
• Consequence: SDHC NM_003001.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.135

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 (BayesDel_noAF=-0.82).
• BP6: Variant 1-161362556-C-G is Benign according to our data. Variant chr1-161362556-C-G is described in ClinVar as [Benign]. Clinvar id is 286523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHC	NM_003001.5	c.*123C>G		3_prime_UTR_variant	6/6	ENST00000367975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHC	ENST00000367975.7	c.*123C>G		3_prime_UTR_variant	6/6	1	NM_003001.5	P1
SDHC	ENST00000342751.8	c.*16C>G		3_prime_UTR_variant	5/5	1
SDHC	ENST00000470743.5	c.*634C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	5
SDHC	ENST00000513009.5			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12852 AN: 152024 Hom.: 645 Cov.: 31

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0726

GnomAD3 exomes AF: 0.0932 AC: 22435 AN: 240726 Hom.: 1387 AF XY: 0.0958 AC XY: 12523 AN XY: 130734

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0789

GnomAD4 exome AF: 0.0749 AC: 108921 AN: 1454954 Hom.: 5509 Cov.: 35 AF XY: 0.0778 AC XY: 56259 AN XY: 723446

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0612

Gnomad4 ASJ exome AF: 0.0299

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.0963

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0732

GnomAD4 genome AF: 0.0845 AC: 12859 AN: 152142 Hom.: 645 Cov.: 31 AF XY: 0.0884 AC XY: 6572 AN XY: 74350

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.0718

Alfa AF: 0.0684 Hom.: 72

Bravo AF: 0.0786

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 25, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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

Other links and lift over

dbSNP: rs3813632; hg19: chr1-161332346; COSMIC: COSV61368310; COSMIC: COSV61368310;