1-161201946-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000367993.7(NDUFS2):c.-239-201A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 216,784 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.013 (13 hom.)
• Consequence: NDUFS2 ENST00000367993.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.194

Genes affected

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-161201946-A-G is Benign according to our data. Variant chr1-161201946-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1207148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2292/152306) while in subpopulation NFE AF= 0.0213 (1448/68020). AF 95% confidence interval is 0.0204. There are 29 homozygotes in gnomad4. There are 1201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS2	NM_001377298.1	c.-239-201A>G		intron_variant
NDUFS2	NM_001377300.1	c.-239-201A>G		intron_variant
NDUFS2	NM_001377301.1	c.-239-201A>G		intron_variant
NDUFS2	NM_004550.5	c.-239-201A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS2	ENST00000367993.7	c.-239-201A>G		intron_variant		1		P1
NDUFS2	ENST00000676600.1	c.-76-364A>G		intron_variant				P1
NDUFS2	ENST00000677231.1	c.-239-201A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2293 AN: 152188 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0134 AC: 861 AN: 64478 Hom.: 13 AF XY: 0.0122 AC XY: 427 AN XY: 35116

Gnomad4 AFR exome AF: 0.00309

Gnomad4 AMR exome AF: 0.00506

Gnomad4 ASJ exome AF: 0.00649

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0181

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0150 AC: 2292 AN: 152306 Hom.: 29 Cov.: 32 AF XY: 0.0161 AC XY: 1201 AN XY: 74480

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0177 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.0
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs115518404; hg19: chr1-161171736;