rs146170087
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_031448.6(C19orf12):āc.391A>Gā(p.Lys131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,932 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K131T) has been classified as Benign.
Frequency
Consequence
NM_031448.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C19orf12 | NM_031448.6 | c.391A>G | p.Lys131Glu | missense_variant | 3/3 | ENST00000323670.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C19orf12 | ENST00000323670.14 | c.391A>G | p.Lys131Glu | missense_variant | 3/3 | 2 | NM_031448.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00122 AC: 186AN: 152142Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00229 AC: 573AN: 250744Hom.: 3 AF XY: 0.00271 AC XY: 368AN XY: 135794
GnomAD4 exome AF: 0.00162 AC: 2367AN: 1461672Hom.: 15 Cov.: 30 AF XY: 0.00190 AC XY: 1379AN XY: 727130
GnomAD4 genome ? AF: 0.00123 AC: 187AN: 152260Hom.: 3 Cov.: 32 AF XY: 0.00130 AC XY: 97AN XY: 74444
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | C19orf12: PM3, PM2:Supporting, BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2021 | This variant is associated with the following publications: (PMID: 30088953, 21981780, 25592411) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Neurodegeneration with brain iron accumulation 4 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Pathogenic, flagged submission | literature only | OMIM | Oct 07, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Dec 03, 2021 | - - |
Hereditary spastic paraplegia 43 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness Pathogenic:1
Pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 01, 2015 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 31, 2017 | - - |
Hereditary spastic paraplegia 5A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | Variant summary: C19orf12 c.391A>G (p.Lys131Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250744 control chromosomes, predominantly at a frequency of 0.0096 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.0006), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign (n=1), likely benign (n=3), uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at