6-24422946-A-G

Position:

• chr6-24422946-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020662.4(MRS2):​c.1117A>G​(p.Ile373Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRS2 NM_020662.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.94

Genes affected

MRS2 (HGNC:13785): (magnesium transporter MRS2) Enables magnesium ion transmembrane transporter activity. Involved in mitochondrial magnesium ion transmembrane transport. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06337431).
• BP6: Variant 6-24422946-A-G is Benign according to our data. Variant chr6-24422946-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3296148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRS2	NM_020662.4	c.1117A>G	p.Ile373Val	missense_variant	10/11	ENST00000378386.8	NP_065713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRS2	ENST00000378386.8	c.1117A>G	p.Ile373Val	missense_variant	10/11	1	NM_020662.4	ENSP00000367637	P1
MRS2	ENST00000378353.5	c.1117A>G	p.Ile373Val	missense_variant	10/10	1		ENSP00000367604
MRS2	ENST00000443868.6	c.1126A>G	p.Ile376Val	missense_variant	11/12	2		ENSP00000399585
MRS2	ENST00000274747.11	c.967A>G	p.Ile323Val	missense_variant	8/9	2		ENSP00000274747

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.2
DANN	Benign	0.60
DEOGEN2	Benign	0.060	.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.79	.;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.57	N;.;N;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.14
MutPred		0.24		.;.;Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.23
MPC		0.29
ClinPred		0.031	T
GERP RS		2.0
Varity_R		0.013
gMVP		0.31

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: rs775875580; hg19: chr6-24423174;