rs189383313

Variant names:

• chr7-76048243-G-A
• rs189383313
• NM_005918.4:c.66+17G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-76048243-G-A
• chr7-76048243-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005918.4(MDH2):​c.66+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 1,531,180 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 35)
  • Exomes 𝑓: 0.0054 (70 hom.)
• Consequence: MDH2 NM_005918.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.02

Genes affected

MDH2 (HGNC:6971): (malate dehydrogenase 2) Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

STYXL1 (HGNC:18165): (serine/threonine/tyrosine interacting like 1) Enables protein phosphatase binding activity; protein phosphatase inhibitor activity; and pseudophosphatase activity. Involved in several processes, including negative regulation of phosphoprotein phosphatase activity; negative regulation of stress granule assembly; and positive regulation of intrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 7-76048243-G-A is Benign according to our data. Variant chr7-76048243-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76048243-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00366 (557/152344) while in subpopulation SAS AF= 0.0207 (100/4830). AF 95% confidence interval is 0.0174. There are 4 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH2	NM_005918.4	c.66+17G>A		intron_variant	Intron 1 of 8	ENST00000315758.10	NP_005909.2
STYXL1	NM_001317785.2	c.-586C>T		upstream_gene_variant		ENST00000359697.8	NP_001304714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH2	ENST00000315758.10	c.66+17G>A		intron_variant	Intron 1 of 8	1	NM_005918.4	ENSP00000327070.5
STYXL1	ENST00000359697.8	c.-586C>T		upstream_gene_variant		1	NM_001317785.2	ENSP00000352726.3

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152226 Hom.: 4 Cov.: 35

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00581 AC: 773 AN: 132952 Hom.: 10 AF XY: 0.00730 AC XY: 528 AN XY: 72368

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0201

Gnomad FIN exome AF: 0.00267

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00539 AC: 7432 AN: 1378836 Hom.: 70 Cov.: 37 AF XY: 0.00597 AC XY: 4058 AN XY: 680016

Gnomad4 AFR exome AF: 0.000737

Gnomad4 AMR exome AF: 0.000929

Gnomad4 ASJ exome AF: 0.00128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00488

Gnomad4 OTH exome AF: 0.00602

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152344 Hom.: 4 Cov.: 35 AF XY: 0.00364 AC XY: 271 AN XY: 74494

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00592 Hom.: 0

Bravo AF: 0.00283

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	10
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs189383313; hg19: chr7-75677561; COSMIC: COSV50390204; COSMIC: COSV50390204;