11-112088901-C-T

Position:

chr11-112088901-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003002.4(SDHD):c.204C>T(p.Ser68Ser) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: -0.482

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.204C>T	p.Ser68Ser	synonymous_variant	3/4	ENST00000375549.8	NP_002993.1	O14521-1A0A0S2Z4J3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.204C>T	p.Ser68Ser	synonymous_variant	3/4	1	NM_003002.4	ENSP00000364699.3		O14521-1
ENSG00000255292	ENST00000532699.1 linkuse as main transcript	n.204C>T		non_coding_transcript_exon_variant	3/6	3		ENSP00000456434.1		H3BRW5

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16088

AN:

152054

Hom.:

2500

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0180

AC XY:

13068

AN XY:

726488

show subpopulations

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.:

AF XY:

0.103

AC XY:

7674

AN XY:

74414

show subpopulations

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:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

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	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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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

Labcorp Genetics (formerly Invitae), Labcorp

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over