5-140647373-G-C

Position:

• chr5-140647373-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_002488.5(NDUFA2):​c.102-11C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,611,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: NDUFA2 NM_002488.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001690
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0520

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:):

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

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-140647373-G-C is Benign according to our data. Variant chr5-140647373-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 380652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA2	NM_002488.5	c.102-11C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000252102.9
TMCO6	XM_047417354.1	c.*556G>C		3_prime_UTR_variant	11/11
NDUFA2	NM_001185012.2	c.102-11C>G		splice_polypyrimidine_tract_variant, intron_variant
NDUFA2	NR_033697.2	n.258C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA2	ENST00000252102.9	c.102-11C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002488.5	P1
NDUFA2	ENST00000512088.1	c.102-11C>G		splice_polypyrimidine_tract_variant, intron_variant		2
IK	ENST00000513256.5	c.4+64G>C		intron_variant		4
NDUFA2	ENST00000502960.1	n.399C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 250368 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135328

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1458796 Hom.: 0 Cov.: 30 AF XY: 0.0000662 AC XY: 48 AN XY: 725038

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000695

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74464

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs201963018; hg19: chr5-140026958;