2-75655100-C-A

Variant names:

• chr2-75655100-C-A
• rs200518280
• NM_014763.4:c.694C>A

Variant summary

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

The NM_014763.4(MRPL19):​c.694C>A​(p.Arg232Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,442 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. R232H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MRPL19 NM_014763.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66
• Publications: 0 publications found

Genes affected

MRPL19 (HGNC:14052): (mitochondrial ribosomal protein L19) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. [provided by RefSeq, Jul 2008]

GCFC2 (HGNC:1317): (GC-rich sequence DNA-binding factor 2) The first mRNA transcript isolated for this gene was part of an artificial chimera derived from two distinct gene transcripts and a primer used in the cloning process (see Genbank accession M29204). A positively charged amino terminus present only in the chimera was determined to bind GC-rich DNA, thus mistakenly thought to identify a transcription factor gene. [provided by RefSeq, Jul 2008]

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014763.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL19	NM_014763.4	MANE Select	c.694C>A	p.Arg232Ser	missense	Exon 6 of 6	NP_055578.2	P49406

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL19	ENST00000393909.7	TSL:1 MANE Select	c.694C>A	p.Arg232Ser	missense	Exon 6 of 6	ENSP00000377486.2	P49406
	MRPL19	ENST00000409374.5	TSL:5	c.694C>A	p.Arg232Ser	missense	Exon 6 of 7	ENSP00000387284.1	P49406
	MRPL19	ENST00000884931.1		c.694C>A	p.Arg232Ser	missense	Exon 6 of 7	ENSP00000554990.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458442 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725540

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109904

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.39		Gain of phosphorylation at R232 (P = 0.0327)
MVP		0.83
MPC		0.53
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.80
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs200518280; hg19: chr2-75882226;