1-161362556-C-G

Variant names:

• chr1-161362556-C-G
• rs3813632
• NM_003001.5:c.*123C>G

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 0.135
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SDHC	NM_003001.5	c.*123C>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.*123C>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_003001.5	ENSP00000356953.3

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

GnomAD2 exomes AF: 0.0932 AC: 22435 AN: 240726 AF XY: 0.0958

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 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

African (AFR) AF: 0.105 AC: 3494 AN: 33368

American (AMR) AF: 0.0612 AC: 2706 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 779 AN: 26032

East Asian (EAS) AF: 0.259 AC: 10250 AN: 39592

South Asian (SAS) AF: 0.178 AC: 15186 AN: 85506

European-Finnish (FIN) AF: 0.0963 AC: 5123 AN: 53208

Middle Eastern (MID) AF: 0.0458 AC: 190 AN: 4150

European-Non Finnish (NFE) AF: 0.0602 AC: 66798 AN: 1108892

Other (OTH) AF: 0.0732 AC: 4395 AN: 60018

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

African (AFR) AF: 0.102 AC: 4251 AN: 41500

American (AMR) AF: 0.0610 AC: 933 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.207 AC: 1069 AN: 5164

South Asian (SAS) AF: 0.183 AC: 883 AN: 4818

European-Finnish (FIN) AF: 0.104 AC: 1094 AN: 10566

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0637 AC: 4332 AN: 67996

Other (OTH) AF: 0.0718 AC: 152 AN: 2116

Alfa AF: 0.0684 Hom.: 72

Bravo AF: 0.0786

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 08, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1+BP6 -

Hereditary pheochromocytoma-paraganglioma Benign:1

Jan 13, 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_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.52
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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