1-161362321-G-T

Variant names:

• chr1-161362321-G-T
• rs747093483
• NM_003001.5:c.406-8G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003001.5(SDHC):​c.406-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0078 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHC NM_003001.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001562
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0700

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-161362321-G-T is Benign according to our data. Variant chr1-161362321-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr1-161362321-G-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5	c.406-8G>T		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.406-8G>T		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 650 AN: 83732 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.00851

Gnomad AMI AF: 0.00568

Gnomad AMR AF: 0.00742

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00360

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.00735

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00935

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00492 AC: 5898 AN: 1197992 Hom.: 0 Cov.: 37 AF XY: 0.00506 AC XY: 3023 AN XY: 597514

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.00699

Gnomad4 EAS exome AF: 0.00699

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.0382

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00470

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00778 AC: 652 AN: 83788 Hom.: 0 Cov.: 25 AF XY: 0.00779 AC XY: 312 AN XY: 40068

Gnomad4 AFR AF: 0.00848

Gnomad4 AMR AF: 0.00754

Gnomad4 ASJ AF: 0.00265

Gnomad4 EAS AF: 0.00305

Gnomad4 SAS AF: 0.00361

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00924

Alfa AF: 0.0496 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 05, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406-8G>T intronic alteration consists of a G to T substitution 8 nucleotides before coding exon 6 in the SDHC gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Dec 19, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Benign:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.72
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs747093483; hg19: chr1-161332111; COSMIC: COSV61367449; COSMIC: COSV61367449;