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GeneBe

11-112086912-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003002.4(SDHD):c.5C>T(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.98
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SDHDNM_003002.4 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/4 ENST00000375549.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SDHDENST00000375549.8 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/41 NM_003002.4 P1O14521-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251424
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 21, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 852212). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the SDHD protein (p.Ala2Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 21, 2022The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the SDHD gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.21
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.;.;.;.;.;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.67
T;T;T;T;T;.;T
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.74
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
2.0
M;M;.;M;.;M;M
MutationTaster
Benign
0.87
D;D;D;D;N
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.5
N;.;N;D;N;N;N
REVEL
Uncertain
0.49
Sift
Benign
0.089
T;.;T;D;T;T;T
Sift4G
Benign
0.27
T;T;T;T;T;T;T
Polyphen
0.039
B;.;.;.;.;.;.
Vest4
0.69
MutPred
0.39
Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);Loss of disorder (P = 0.0366);
MVP
0.99
MPC
0.36
ClinPred
0.93
D
GERP RS
4.3
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.10
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1440670464; hg19: chr11-111957636; COSMIC: COSV54778335; COSMIC: COSV54778335; API