1-161362321-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

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:1B:5

Conservation

PhyloP100: -0.0700

Publications

0 publications found

Variant links:

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

SDHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.406-8G>T		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000367975.7	NP_002992.1	Q99643-1A0A0S2Z4B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 link	c.406-8G>T		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00776

AC:

650

AN:

83732

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00773

AC:

1443

AN:

186702

AF XY:

0.00756

show subpopulations

Gnomad AFR exome

AF:

0.00847

Gnomad AMR exome

AF:

0.00396

Gnomad ASJ exome

AF:

0.00703

Gnomad EAS exome

AF:

0.00543

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.00909

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00492

AC:

5898

AN:

1197992

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

3023

AN XY:

597514

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0115

AC:

297

AN:

25876

American (AMR)

AF:

0.0226

AC:

728

AN:

32198

Ashkenazi Jewish (ASJ)

AF:

0.00699

AC:

154

AN:

22030

East Asian (EAS)

AF:

0.00699

AC:

226

AN:

32334

South Asian (SAS)

AF:

0.0100

AC:

637

AN:

63724

European-Finnish (FIN)

AF:

0.0382

AC:

1683

AN:

44114

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

3584

European-Non Finnish (NFE)

AF:

0.00205

AC:

1897

AN:

924754

Other (OTH)

AF:

0.00470

AC:

232

AN:

49378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.245

Heterozygous variant carriers

901

1802

2702

3603

4504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00778

AC:

652

AN:

83788

Hom.:

Cov.:

AF XY:

0.00779

AC XY:

312

AN XY:

40068

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00848

AC:

175

AN:

20630

American (AMR)

AF:

0.00754

AC:

AN:

7694

Ashkenazi Jewish (ASJ)

AF:

0.00265

AC:

AN:

2266

East Asian (EAS)

AF:

0.00305

AC:

AN:

2950

South Asian (SAS)

AF:

0.00361

AC:

AN:

2770

European-Finnish (FIN)

AF:

0.0270

AC:

130

AN:

4806

Middle Eastern (MID)

AF:

0.00769

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.00610

AC:

249

AN:

40824

Other (OTH)

AF:

0.00924

AC:

AN:

1190

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.261

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0496

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pheochromocytoma/paraganglioma syndrome 3

Benign:1

Mar 17, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Benign:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Benign

0.73

PhyloP100

-0.070

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over