11-112088901-C-T

Variant names:

• chr11-112088901-C-T
• rs9919552
• NM_003002.4:c.204C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -0.482
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 44650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	NM_003002.4	MANE Select	c.204C>T	p.Ser68Ser	synonymous	Exon 3 of 4	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.204C>T	p.Ser68Ser	synonymous	Exon 3 of 5	NP_001263435.1	O14521-4
	SDHD	NM_001276504.2		c.87C>T	p.Ser29Ser	synonymous	Exon 2 of 3	NP_001263433.1	O14521-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.204C>T	p.Ser68Ser	synonymous	Exon 3 of 4	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.169+928C>T		intron	N/A	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.204C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000456434.1	H3BRW5

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

GnomAD2 exomes AF: 0.0341 AC: 8571 AN: 251246 AF XY: 0.0272

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 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

African (AFR) AF: 0.365 AC: 12194 AN: 33398

American (AMR) AF: 0.0286 AC: 1277 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 377 AN: 26134

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39700

South Asian (SAS) AF: 0.00396 AC: 341 AN: 86184

European-Finnish (FIN) AF: 0.00451 AC: 241 AN: 53420

Middle Eastern (MID) AF: 0.0455 AC: 213 AN: 4678

European-Non Finnish (NFE) AF: 0.0105 AC: 11626 AN: 1111830

Other (OTH) AF: 0.0339 AC: 2045 AN: 60250

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

African (AFR) AF: 0.344 AC: 14259 AN: 41466

American (AMR) AF: 0.0497 AC: 760 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5172

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 800 AN: 68012

Other (OTH) AF: 0.0806 AC: 170 AN: 2108

Alfa AF: 0.0504 Hom.: 220

Bravo AF: 0.121

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	3	Pheochromocytoma/paraganglioma syndrome 1 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Pheochromocytoma (2)
-	-	1	Carney-Stratakis syndrome;C3494181:Pheochromocytoma/paraganglioma syndrome 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Mitochondrial complex 2 deficiency, nuclear type 3 (1)
-	-	1	Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.5
DANN	Benign	0.78
PhyloP100		-0.48
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9919552; hg19: chr11-111959625;