2-75655055-C-G

Variant names:

• chr2-75655055-C-G
• rs775408727
• NM_014763.4:c.658-9C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014763.4(MRPL19):​c.658-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 641,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MRPL19 NM_014763.4 intron
• Scores: Splicing: ADA: 0.0006958
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.574
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

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.658-9C>G		intron	N/A	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.658-9C>G		intron	N/A	ENSP00000377486.2	P49406
	MRPL19	ENST00000409374.5	TSL:5	c.658-9C>G		intron	N/A	ENSP00000387284.1	P49406
	MRPL19	ENST00000884931.1		c.658-9C>G		intron	N/A	ENSP00000554990.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000125 AC: 8 AN: 641106 Hom.: 0 Cov.: 19 AF XY: 0.0000154 AC XY: 5 AN XY: 324618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13810

American (AMR) AF: 0.00 AC: 0 AN: 16440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13310

East Asian (EAS) AF: 0.00 AC: 0 AN: 24676

South Asian (SAS) AF: 0.0000306 AC: 1 AN: 32666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2046

European-Non Finnish (NFE) AF: 0.0000148 AC: 7 AN: 472348

Other (OTH) AF: 0.00 AC: 0 AN: 28016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		0.57
PromoterAI		-0.0012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00070
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.080		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: rs775408727; hg19: chr2-75882181;