11-112088901-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003002.4(SDHD):c.204C>T(p.Ser68=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,612,482 control chromosomes in the GnomAD database, including 5,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2531 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2512 hom.)
• Consequence: SDHD NM_003002.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.482

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-112088901-C-T is Benign according to our data. Variant chr11-112088901-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088901-C-T is described in Lovd as [Likely_benign]. Variant chr11-112088901-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.482 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.204C>T	p.Ser68=	synonymous_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.204C>T	p.Ser68=	synonymous_variant	3/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16088 AN: 152054 Hom.: 2500 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0815

GnomAD3 exomes AF: 0.0341 AC: 8571 AN: 251246 Hom.: 1053 AF XY: 0.0272 AC XY: 3696 AN XY: 135790

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00190

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0194 AC: 28359 AN: 1460310 Hom.: 2512 Cov.: 32 AF XY: 0.0180 AC XY: 13068 AN XY: 726488

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.0286

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.00396

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.0339

GnomAD4 genome AF: 0.106 AC: 16161 AN: 152172 Hom.: 2531 Cov.: 32 AF XY: 0.103 AC XY: 7674 AN XY: 74414

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.0497

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0806

Alfa AF: 0.0389 Hom.: 220

Bravo AF: 0.121

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2012	This variant is classified as benign because it does not change the amino acid a nd is frequent in the general population (rs9919552, MAF >1%). Noted as 2.8-4.4% in TCA gene mutation database. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The SDHD c.204C>T (p.Ser68Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. This variant was found in 4824/121320 control chromosomes (622 homozygotes), predominantly observed in the African subpopulation (610 homozygotes) at a frequency of 0.3507319 (3642/10384). This frequency is greatly exceeds the estimated maximal expected allele frequency of a pathogenic SDHD variant (0.0000016), suggesting this is a common benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories have classified this variant as Benign/Likely Benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Pheochromocytoma Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Paragangliomas 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Mitochondrial complex 2 deficiency, nuclear type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Paragangliomas 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.5
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs9919552; hg19: chr11-111959625;