chr1-161362343-A-C

Variant names:

• chr1-161362343-A-C
• rs794727791
• ENST00000342751.8:c.256A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000342751.8(SDHC):​c.256A>C​(p.Lys86Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K86E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHC ENST00000342751.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13638017).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000342751.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	NM_003001.5	MANE Select	c.420A>C	p.Gly140Gly	synonymous	Exon 6 of 6	NP_002992.1
	SDHC	NM_001035511.3		c.256A>C	p.Lys86Gln	missense	Exon 5 of 5	NP_001030588.1
	SDHC	NM_001407121.1		c.199A>C	p.Lys67Gln	missense	Exon 4 of 4	NP_001394050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	ENST00000342751.8	TSL:1	c.256A>C	p.Lys86Gln	missense	Exon 5 of 5	ENSP00000356952.3
	SDHC	ENST00000513009.5	TSL:1	c.154A>C	p.Lys52Gln	missense	Exon 4 of 4	ENSP00000423260.1
	SDHC	ENST00000367975.7	TSL:1 MANE Select	c.420A>C	p.Gly140Gly	synonymous	Exon 6 of 6	ENSP00000356953.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461472 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727044

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	3.9
DANN	Benign	0.84
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.19	D
PhyloP100		-0.24
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.27	T
Polyphen		0.42	B
Vest4		0.25
MutPred		0.13		Loss of ubiquitination at K86 (P = 0.0118)
MVP		0.89
ClinPred		0.17	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs794727791; hg19: chr1-161332133;