Genetic Variant SDHD:p.Gly12Ser (chr11-112086941-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_003002.4(SDHD):c.34G>A(p.Gly12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 1,614,148 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 68 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:29O:1

Conservation

PhyloP100: -0.230

Publications

59 publications found

Variant links:

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

SDHD links:

ENSG00000255292 (HGNC:):

ENSG00000255292 links:

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

TIMM8B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 42 uncertain in NM_003002.4

BP4

Computational evidence support a benign effect (MetaRNN=0.056276977).

BP6

Variant 11-112086941-G-A is Benign according to our data. Variant chr11-112086941-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6895.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00705 (1073/152298) while in subpopulation AMR AF = 0.0116 (177/15300). AF 95% confidence interval is 0.0102. There are 5 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003002.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHD	NM_003002.4	MANE Select	c.34G>A	p.Gly12Ser	missense	Exon 1 of 4	NP_002993.1	O14521-1
SDHD	NM_001276506.2		c.34G>A	p.Gly12Ser	missense	Exon 1 of 5	NP_001263435.1	O14521-4
SDHD	NM_001276504.2		c.34G>A	p.Gly12Ser	missense	Exon 1 of 3	NP_001263433.1	O14521-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHD	ENST00000375549.8	TSL:1 MANE Select	c.34G>A	p.Gly12Ser	missense	Exon 1 of 4	ENSP00000364699.3	O14521-1
SDHD	ENST00000528048.5	TSL:1	c.34G>A	p.Gly12Ser	missense	Exon 1 of 3	ENSP00000436217.1	O14521-3
ENSG00000255292	ENST00000532699.1	TSL:3	n.34G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1073

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00992

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00749

AC:

1882

AN:

251370

AF XY:

0.00754

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00911

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.00854

AC:

12482

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00842

AC XY:

6125

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

33480

American (AMR)

AF:

0.00991

AC:

443

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00987

AC:

258

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00290

AC:

250

AN:

86258

European-Finnish (FIN)

AF:

0.00427

AC:

228

AN:

53396

Middle Eastern (MID)

AF:

0.0222

AC:

128

AN:

5768

European-Non Finnish (NFE)

AF:

0.00954

AC:

10608

AN:

1112000

Other (OTH)

AF:

0.00866

AC:

523

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

782

1563

2345

3126

3908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.00705

AC:

1073

AN:

152298

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

487

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41586

American (AMR)

AF:

0.0116

AC:

177

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00480

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00992

AC:

675

AN:

68012

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00933

Hom.:

Bravo

AF:

0.00804

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0112

AC:

ExAC

AF:

0.00726

AC:

881

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0114

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (12)

not provided (6)

Hereditary cancer-predisposing syndrome (3)

Pheochromocytoma/paraganglioma syndrome 1 (3)

Pheochromocytoma (2)

Carney-Stratakis syndrome (1)

Carney-Stratakis syndrome;C3494181:Pheochromocytoma/paraganglioma syndrome 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 (1)

Cowden syndrome 3 (1)

Hereditary pheochromocytoma and paraganglioma (1)

Mitochondrial complex 2 deficiency, nuclear type 3 (1)

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.18

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

MetaRNN

Benign

0.056

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.5

PhyloP100

-0.23

PrimateAI

Benign

0.39

PROVEAN

Benign

0.21

REVEL

Uncertain

0.57

Sift

Benign

0.40

Sift4G

Benign

0.77

Polyphen

0.0050

Vest4

0.14

MVP

1.0

MPC

0.19

ClinPred

0.011

GERP RS

-7.3

PromoterAI

-0.089

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.050

gMVP

0.48

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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