dbSNP rs182629842: SDHC:p.Ala142Thr (chr1-161362511-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035511.3(SDHC):c.424G>A(p.Ala142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,610,112 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

SDHC
NM_001035511.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:2B:8

Conservation

PhyloP100: 1.95

Publications

3 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: 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

SDHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072749257).

BP6

Variant 1-161362511-G-A is Benign according to our data. Variant chr1-161362511-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 41772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00176 (267/152088) while in subpopulation AMR AF = 0.00281 (43/15282). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 267 AD,Unknown 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHC	NM_003001.5	MANE Select	c.*78G>A		3_prime_UTR	Exon 6 of 6	NP_002992.1	Q99643-1
SDHC	NM_001035511.3		c.424G>A	p.Ala142Thr	missense	Exon 5 of 5	NP_001030588.1	Q99643-2
SDHC	NM_001407121.1		c.367G>A	p.Ala123Thr	missense	Exon 4 of 4	NP_001394050.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHC	ENST00000342751.8	TSL:1	c.424G>A	p.Ala142Thr	missense	Exon 5 of 5	ENSP00000356952.3	Q99643-2
SDHC	ENST00000513009.5	TSL:1	c.322G>A	p.Ala108Thr	missense	Exon 4 of 4	ENSP00000423260.1	Q99643-4
SDHC	ENST00000367975.7	TSL:1 MANE Select	c.*78G>A		3_prime_UTR	Exon 6 of 6	ENSP00000356953.3	Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00169

AC:

403

AN:

237948

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.000265

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00264

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00123

Gnomad NFE exome

AF:

0.00257

Gnomad OTH exome

AF:

0.00307

GnomAD4 exome

AF:

0.00214

AC:

3122

AN:

1458024

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1502

AN XY:

725248

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33382

American (AMR)

AF:

0.00144

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000547

AC:

AN:

85944

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.000686

AC:

AN:

4370

European-Non Finnish (NFE)

AF:

0.00244

AC:

2714

AN:

1110648

Other (OTH)

AF:

0.00229

AC:

138

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

163

325

488

650

813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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

AF:

0.00176

AC:

267

AN:

152088

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41450

American (AMR)

AF:

0.00281

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00257

AC:

175

AN:

67992

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00203

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.000462

AC:

ESP6500EA

AF:

0.00235

AC:

ExAC

AF:

0.00167

AC:

202

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary pheochromocytoma and paraganglioma (2)

Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)

Hereditary cancer-predisposing syndrome (1)

not specified (1)

SDHC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

5.3

(source)

DANN

Benign

0.53

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.0073

MetaSVM

Uncertain

-0.23

PhyloP100

2.0

PROVEAN

Benign

0.12

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.20

MVP

0.80

ClinPred

0.025

GERP RS

1.8

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over