rs146170087

Positions:

• chr19-29702747-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_031448.6(C19orf12):​c.391A>G​(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:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (15 hom.)
• Consequence: C19orf12 NM_031448.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:8 O:1
• Conservation: PhyloP100: 1.51

Genes affected

C19orf12 (HGNC:25443): (chromosome 19 open reading frame 12) This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 29 pathogenic changes around while only 10 benign (74%) in NM_031448.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.007799536).
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

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: 186 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00229 AC: 573 AN: 250744 Hom.: 3 AF XY: 0.00271 AC XY: 368 AN XY: 135794

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00162 AC: 2367 AN: 1461672 Hom.: 15 Cov.: 30 AF XY: 0.00190 AC XY: 1379 AN XY: 727130

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00934

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74444

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00140 Hom.: 2

Bravo AF: 0.00124

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

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:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;.;.;D
MetaRNN	Benign	0.0078	T;T;T;T;T
MetaSVM	Uncertain	-0.017	T
MutationTaster	Benign	0.97	D;D;D;D
Sift4G	Uncertain	0.017	D;T;T;D;T
Vest4		0.30
MVP		0.40
MPC		0.70
ClinPred		0.028	T
GERP RS		3.0
Varity_R		0.41
gMVP		0.47

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: rs146170087; hg19: chr19-30193654;