5-228247-T-C

Variant names:

• chr5-228247-T-C
• rs2115272
• NM_004168.4:c.684T>C

Variant summary

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

The NM_004168.4(SDHA):​c.684T>C​(p.Asn228Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,360 control chromosomes in the GnomAD database, including 24,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6853 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17252 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.866
• Publications: 26 publications found

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-228247-T-C is Benign according to our data. Variant chr5-228247-T-C is described in ClinVar as Benign. ClinVar VariationId is 130282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.866 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. 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
	SDHA	NM_004168.4	MANE Select	c.684T>C	p.Asn228Asn	synonymous	Exon 6 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.540T>C	p.Asn180Asn	synonymous	Exon 5 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.684T>C	p.Asn228Asn	synonymous	Exon 6 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.684T>C	p.Asn228Asn	synonymous	Exon 6 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.684T>C		non_coding_transcript_exon	Exon 6 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.684T>C	p.Asn228Asn	synonymous	Exon 6 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36476 AN: 151916 Hom.: 6826 Cov.: 32

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0561

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.152 AC: 38267 AN: 251138 AF XY: 0.143

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0608

Gnomad FIN exome AF: 0.0862

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.137 AC: 199974 AN: 1461326 Hom.: 17252 Cov.: 32 AF XY: 0.134 AC XY: 97550 AN XY: 727006

African (AFR) AF: 0.542 AC: 18134 AN: 33458

American (AMR) AF: 0.188 AC: 8428 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4305 AN: 26130

East Asian (EAS) AF: 0.0480 AC: 1907 AN: 39700

South Asian (SAS) AF: 0.0901 AC: 7768 AN: 86242

European-Finnish (FIN) AF: 0.0885 AC: 4730 AN: 53420

Middle Eastern (MID) AF: 0.138 AC: 798 AN: 5762

European-Non Finnish (NFE) AF: 0.130 AC: 144508 AN: 1111532

Other (OTH) AF: 0.156 AC: 9396 AN: 60368

GnomAD4 genome AF: 0.240 AC: 36548 AN: 152034 Hom.: 6853 Cov.: 32 AF XY: 0.235 AC XY: 17437 AN XY: 74292

African (AFR) AF: 0.525 AC: 21731 AN: 41408

American (AMR) AF: 0.220 AC: 3365 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.0556 AC: 288 AN: 5176

South Asian (SAS) AF: 0.0889 AC: 428 AN: 4812

European-Finnish (FIN) AF: 0.0819 AC: 866 AN: 10580

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8475 AN: 67982

Other (OTH) AF: 0.229 AC: 482 AN: 2108

Alfa AF: 0.179 Hom.: 1584

Bravo AF: 0.267

Asia WGS AF: 0.114 AC: 401 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.135

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.091
DANN	Benign	0.26
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2115272; hg19: chr5-228362; COSMIC: COSV53765870; COSMIC: COSV53765870;