rs201210474

Variant names:

• chr1-161362517-G-C
• rs201210474
• ENST00000342751.8:c.430G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035511.3(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. 13/18 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 NM_001035511.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11 O:1
• Conservation: PhyloP100: -0.389
• Publications: 17 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: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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 -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 VariationId is 41773.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1037 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035511.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	NM_003001.5	MANE Select	c.*84G>C		3_prime_UTR	Exon 6 of 6	NP_002992.1	Q99643-1
	SDHC	NM_001035511.3		c.430G>C	p.Glu144Gln	missense	Exon 5 of 5	NP_001030588.1	Q99643-2
	SDHC	NM_001407121.1		c.373G>C	p.Glu125Gln	missense	Exon 4 of 4	NP_001394050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	ENST00000342751.8	TSL:1	c.430G>C	p.Glu144Gln	missense	Exon 5 of 5	ENSP00000356952.3	Q99643-2
	SDHC	ENST00000513009.5	TSL:1	c.328G>C	p.Glu110Gln	missense	Exon 4 of 4	ENSP00000423260.1	Q99643-4
	SDHC	ENST00000367975.7	TSL:1 MANE Select	c.*84G>C		3_prime_UTR	Exon 6 of 6	ENSP00000356953.3	Q99643-1

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1037 AN: 152060 Hom.: 10 Cov.: 31

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

GnomAD2 exomes AF: 0.00536 AC: 1268 AN: 236416 AF XY: 0.00518

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 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.: 80 Cov.: 35 AF XY: 0.0111 AC XY: 8073 AN XY: 724684

African (AFR) AF: 0.00186 AC: 62 AN: 33374

American (AMR) AF: 0.00269 AC: 119 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00495 AC: 129 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000221 AC: 19 AN: 85852

European-Finnish (FIN) AF: 0.00240 AC: 128 AN: 53296

Middle Eastern (MID) AF: 0.000927 AC: 4 AN: 4316

European-Non Finnish (NFE) AF: 0.0140 AC: 15596 AN: 1110064

Other (OTH) AF: 0.0103 AC: 617 AN: 60124

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152178 Hom.: 10 Cov.: 31 AF XY: 0.00606 AC XY: 451 AN XY: 74398

African (AFR) AF: 0.00251 AC: 104 AN: 41506

American (AMR) AF: 0.00392 AC: 60 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 806 AN: 68012

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00754 Hom.: 1

Bravo AF: 0.00713

ESP6500AA AF: 0.00187 AC: 8

ESP6500EA AF: 0.00813 AC: 69

ExAC AF: 0.00489 AC: 592

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (3)
-	-	1	Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
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	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	-0.20	T
PhyloP100		-0.39
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.26	B
Vest4		0.16
MVP		0.81
ClinPred		0.0048	T
GERP RS		1.1
Mutation Taster		=99/1	polymorphism

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: rs201210474; hg19: chr1-161332307; COSMIC: COSV105907666;