5-140647544-G-C

Variant names:

• chr5-140647544-G-C
• rs35672074
• NM_002488.5:c.40C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_002488.5(NDUFA2):​c.40C>G​(p.Leu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,611,968 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. L14Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: NDUFA2 NM_002488.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.283
• Publications: 6 publications found

Genes affected

NDUFA2 (HGNC:7685): (NADH:ubiquinone oxidoreductase subunit A2) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

TMCO6 (HGNC:28814): (transmembrane and coiled-coil domains 6) Predicted to enable nuclear import signal receptor activity. Predicted to be involved in protein import into nucleus. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

IK (HGNC:5958): (IK cytokine) The protein encoded by this gene was identified by its RED repeat, a stretch of repeated arginine, glutamic acid and aspartic acid residues. The protein localizes to discrete dots within the nucleus, excluding the nucleolus. Its function is unknown. This gene maps to chromosome 5; however, a pseudogene may exist on chromosome 2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.24046 (below the threshold of 3.09). Trascript score misZ: -0.5731 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 13, Leigh syndrome, cystic leukoencephalopathy without megalencephaly, Leigh syndrome with leukodystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026907027).
• BP6: Variant 5-140647544-G-C is Benign according to our data. Variant chr5-140647544-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138445.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002488.5. 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
	NDUFA2	NM_002488.5	MANE Select	c.40C>G	p.Leu14Val	missense	Exon 1 of 3	NP_002479.1	O43678-1
	NDUFA2	NM_001185012.2		c.40C>G	p.Leu14Val	missense	Exon 1 of 3	NP_001171941.1	O43678-2
	NDUFA2	NR_033697.2		n.87C>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA2	ENST00000252102.9	TSL:1 MANE Select	c.40C>G	p.Leu14Val	missense	Exon 1 of 3	ENSP00000252102.5	O43678-1
	NDUFA2	ENST00000512088.1	TSL:2	c.40C>G	p.Leu14Val	missense	Exon 1 of 3	ENSP00000427220.1	O43678-2
	IK	ENST00000513256.5	TSL:4	c.4+235G>C		intron	N/A	ENSP00000425564.1	D6RCQ4

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00158 AC: 392 AN: 247786 AF XY: 0.00144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00978

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00110 AC: 1611 AN: 1459636 Hom.: 8 Cov.: 30 AF XY: 0.00111 AC XY: 808 AN XY: 726264

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00910 AC: 466 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000927 AC: 1031 AN: 1111988

Other (OTH) AF: 0.000977 AC: 59 AN: 60378

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74488

African (AFR) AF: 0.0000240 AC: 1 AN: 41596

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.000574

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00153 AC: 186

EpiCase AF: 0.000818

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	NDUFA2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.28
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.050
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.058
MVP		0.10
MPC		0.36
ClinPred		0.018	T
GERP RS		-1.8
PromoterAI		-0.12	Neutral
Varity_R		0.098
gMVP		0.42
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35672074; hg19: chr5-140027129;