rs780512983

Variant names:

• chr10-72368236-C-A
• rs780512983
• NM_001195518.2:c.1390G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-72368236-C-A
• chr10-72368236-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001195518.2(MICU1):​c.1390G>T​(p.Ala464Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A464V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MICU1 NM_001195518.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

Genes affected

MICU1 (HGNC:1530): (mitochondrial calcium uptake 1) This gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2013]

MICU1 Gene-Disease associations (from GenCC):

• proximal myopathy with extrapyramidal signs

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICU1	NM_001195518.2	c.1390G>T	p.Ala464Ser	missense_variant	Exon 12 of 12	ENST00000361114.10	NP_001182447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICU1	ENST00000361114.10	c.1390G>T	p.Ala464Ser	missense_variant	Exon 12 of 12	1	NM_001195518.2	ENSP00000354415.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N;N;.;.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.066	T;D;.;.;T;T
Sift4G	Uncertain	0.060	T;T;.;T;D;D
Polyphen		0.97, 0.93	.;D;.;.;P;P
Vest4		0.66
MutPred		0.36		.;Gain of helix (P = 0.0034);.;.;.;.;
MVP		0.61
MPC		0.61
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.63
gMVP		0.87
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs780512983; hg19: chr10-74127994;