5-218372-G-C

Variant names:

• chr5-218372-G-C
• rs187964306
• NM_004168.4:c.17G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004168.4(SDHA):​c.17G>C​(p.Gly6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,304,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.08
• Publications: 6 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]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03605482).
• BP6: Variant 5-218372-G-C is Benign according to our data. Variant chr5-218372-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 862272.

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.17G>C	p.Gly6Ala	missense	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.17G>C	p.Gly6Ala	missense	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.17G>C	p.Gly6Ala	missense	Exon 1 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.17G>C	p.Gly6Ala	missense	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.17G>C		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.17G>C	p.Gly6Ala	missense	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1304750 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644204

African (AFR) AF: 0.00 AC: 0 AN: 26818

American (AMR) AF: 0.00 AC: 0 AN: 24942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20288

East Asian (EAS) AF: 0.00 AC: 0 AN: 31056

South Asian (SAS) AF: 0.00 AC: 0 AN: 65358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045446

Other (OTH) AF: 0.0000187 AC: 1 AN: 53410

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.10
DANN	Benign	0.52
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		-2.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.33		Gain of helix (P = 0.0164)
MVP		0.076
MPC		0.52
ClinPred		0.057	T
GERP RS		-1.9
PromoterAI		-0.048	Neutral
Varity_R		0.023
gMVP		0.57
Mutation Taster		=100/0	polymorphism

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: rs187964306; hg19: chr5-218487;