19-29702746-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_031448.6(C19orf12):c.392A>C(p.Lys131Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,613,924 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K131E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0056 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 274 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.624

Variant links:

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]

C19orf12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 18 pathogenic changes around while only 7 benign (72%) in NM_031448.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0017057657).

BP6

Variant 19-29702746-T-G is Benign according to our data. Variant chr19-29702746-T-G is described in ClinVar as [Benign]. Clinvar id is 128538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C19orf12	NM_031448.6 link	c.392A>C	p.Lys131Thr	missense_variant	Exon 3 of 3	ENST00000323670.14	NP_113636.2	Q9NSK7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 link	c.392A>C	p.Lys131Thr	missense_variant	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9		Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.00562

AC:

855

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0947

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.0158

AC:

3968

AN:

250742

Hom.:

159

AF XY:

0.0131

AC XY:

1780

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.000562

Gnomad AMR exome

AF:

0.0576

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.0955

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.00703

GnomAD4 exome

AF:

0.00480

AC:

7022

AN:

1461664

Hom.:

274

Cov.:

AF XY:

0.00448

AC XY:

3254

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0504

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.0995

Gnomad4 SAS exome

AF:

0.00199

Gnomad4 FIN exome

AF:

0.00308

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.00436

GnomAD4 genome

AF:

0.00560

AC:

853

AN:

152260

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.0161

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0947

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.0122

Hom.:

330

Bravo

AF:

0.00852

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0141

AC:

1707

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project and 1000 Genomes Project, or Exome Aggregation Consortium. -

Feb 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Hereditary spastic paraplegia 43

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodegeneration with brain iron accumulation 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spastic paraplegia

Benign:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;D;.;.;D

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

.;.;.;.;M

PROVEAN

Uncertain

-3.3

.;.;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.015

.;.;D;D;D

Sift4G

Uncertain

0.013

D;T;T;D;T

Vest4

0.17

MPC

0.44

ClinPred

0.029

GERP RS

2.0

Varity_R

0.24

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over