chr11-112088838-A-G

Variant names:

• chr11-112088838-A-G
• rs9919624
• NM_003002.4:c.170-29A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003002.4(SDHD):​c.170-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,611,516 control chromosomes in the GnomAD database, including 5,040 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 (2532 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2508 hom.)
• Consequence: SDHD NM_003002.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.22
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-112088838-A-G is Benign according to our data. Variant chr11-112088838-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.170-29A>G		intron	N/A	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.170-29A>G		intron	N/A	NP_001263435.1	O14521-4
	SDHD	NM_001276504.2		c.53-29A>G		intron	N/A	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.170-29A>G		intron	N/A	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.169+865A>G		intron	N/A	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.170-29A>G		intron	N/A	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16101 AN: 152114 Hom.: 2501 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0341 AC: 8552 AN: 251018 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: 0.0193 AC: 28183 AN: 1459284 Hom.: 2508 Cov.: 31 AF XY: 0.0179 AC XY: 12978 AN XY: 726000

African (AFR) AF: 0.365 AC: 12154 AN: 33294

American (AMR) AF: 0.0284 AC: 1270 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 377 AN: 26130

East Asian (EAS) AF: 0.00111 AC: 44 AN: 39698

South Asian (SAS) AF: 0.00392 AC: 338 AN: 86160

European-Finnish (FIN) AF: 0.00451 AC: 241 AN: 53414

Middle Eastern (MID) AF: 0.0431 AC: 179 AN: 4154

European-Non Finnish (NFE) AF: 0.0104 AC: 11548 AN: 1111540

Other (OTH) AF: 0.0338 AC: 2032 AN: 60184

GnomAD4 genome AF: 0.106 AC: 16174 AN: 152232 Hom.: 2532 Cov.: 32 AF XY: 0.103 AC XY: 7687 AN XY: 74444

African (AFR) AF: 0.344 AC: 14272 AN: 41498

American (AMR) AF: 0.0496 AC: 759 AN: 15302

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

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10620

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0118 AC: 800 AN: 68018

Other (OTH) AF: 0.0809 AC: 171 AN: 2114

Alfa AF: 0.0355 Hom.: 317

Bravo AF: 0.121

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Pheochromocytoma/paraganglioma syndrome 1 (2)
-	-	1	Mitochondrial complex 2 deficiency, nuclear type 3 (1)
-	-	1	not specified (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9919624; hg19: chr11-111959562;