rs11214077

Variant names:

• chr11-112087953-A-G
• rs11214077
• NM_003002.4:c.149A>G
• SDHD p.His50Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-112087953-A-G
• chr11-112087953-A-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003002.4(SDHD):​c.149A>G​(p.His50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,609,602 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H50D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (48 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:25 O:1
• Conservation: PhyloP100: 2.52
• Publications: 58 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: ClinGen, Orphanet
• pheochromocytoma

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112087952-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431847.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00989148).
• BP6: Variant 11-112087953-A-G is Benign according to our data. Variant chr11-112087953-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00679 (1034/152244) while in subpopulation AMR AF = 0.0155 (237/15302). AF 95% confidence interval is 0.0139. There are 6 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.149A>G	p.His50Arg	missense	Exon 2 of 4	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.149A>G	p.His50Arg	missense	Exon 2 of 5	NP_001263435.1	O14521-4
	SDHD	NM_001276503.2		c.149A>G	p.His50Arg	missense	Exon 2 of 3	NP_001263432.1	A0A0S2Z4H7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.149A>G	p.His50Arg	missense	Exon 2 of 4	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.149A>G	p.His50Arg	missense	Exon 2 of 3	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.149A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1035 AN: 152126 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00796

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00661 AC: 1661 AN: 251460 AF XY: 0.00670

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00734

Gnomad ASJ exome AF: 0.00833

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00741 AC: 10795 AN: 1457358 Hom.: 48 Cov.: 29 AF XY: 0.00729 AC XY: 5289 AN XY: 725300

African (AFR) AF: 0.00141 AC: 47 AN: 33384

American (AMR) AF: 0.00827 AC: 370 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 229 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00183 AC: 158 AN: 86180

European-Finnish (FIN) AF: 0.00673 AC: 359 AN: 53376

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5764

European-Non Finnish (NFE) AF: 0.00822 AC: 9107 AN: 1107874

Other (OTH) AF: 0.00816 AC: 492 AN: 60274

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152244 Hom.: 6 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74448

African (AFR) AF: 0.00212 AC: 88 AN: 41546

American (AMR) AF: 0.0155 AC: 237 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00796 AC: 541 AN: 67992

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.00776 Hom.: 26

Bravo AF: 0.00776

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0100

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	8	not provided (9)
-	-	5	not specified (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Hereditary pheochromocytoma and paraganglioma (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 1 (2)
-	1	-	Carcinoid tumor of intestine (1)
-	-	1	Carney-Stratakis syndrome (1)
-	-	1	Carney-Stratakis syndrome;C3494181:Pheochromocytoma/paraganglioma syndrome 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 (1)
-	-	1	Pheochromocytoma (1)
-	-	1	Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 (1)
-	-	1	SDHD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.68
Sift	Benign	0.065	T
Sift4G	Benign	0.13	T
Varity_R		0.18
gMVP		0.83
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11214077;

hg19: chr11-111958677;