rs1168752295

Variant names:

• chr5-140647251-C-G
• rs1168752295
• NM_002488.5:c.208+5G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-140647251-C-G
• chr5-140647251-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002488.5(NDUFA2):​c.208+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000072 in 1,388,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NDUFA2 NM_002488.5 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.66
• Publications: 0 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]

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA2	NM_002488.5	c.208+5G>C		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000252102.9	NP_002479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA2	ENST00000252102.9	c.208+5G>C		splice_region_variant, intron_variant	Intron 2 of 2	1	NM_002488.5	ENSP00000252102.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388548 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 682692

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31178

American (AMR) AF: 0.00 AC: 0 AN: 34314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21146

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.00 AC: 0 AN: 73776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076236

Other (OTH) AF: 0.00 AC: 0 AN: 57092

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.87
PhyloP100		6.7
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 5

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

Other links and lift over

dbSNP: rs1168752295; hg19: chr5-140026836;