19-29702746-T-G

Variant names:

• chr19-29702746-T-G
• rs79915936
• NM_031448.6:c.392A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.624
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 4

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Illumina, Ambry Genetics, G2P
• hereditary spastic paraplegia 43

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 1.0658 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodegeneration with brain iron accumulation 4, hereditary spastic paraplegia 43.
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031448.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	NM_031448.6	MANE Select	c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	NP_113636.2
	C19orf12	NM_001031726.4		c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	NP_001026896.3
	C19orf12	NM_001256047.2		c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	NP_001242976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	ENSP00000313332.9
	C19orf12	ENST00000392276.1	TSL:1	c.200A>C	p.Lys67Thr	missense	Exon 2 of 2	ENSP00000376102.1
	C19orf12	ENST00000592153.5	TSL:1	c.*13A>C		3_prime_UTR	Exon 4 of 4	ENSP00000467117.1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152142 Hom.: 34 Cov.: 32

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

GnomAD2 exomes AF: 0.0158 AC: 3968 AN: 250742 AF XY: 0.0131

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 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.: 30 AF XY: 0.00448 AC XY: 3254 AN XY: 727124

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.0504 AC: 2256 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0995 AC: 3950 AN: 39700

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86254

European-Finnish (FIN) AF: 0.00308 AC: 164 AN: 53218

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1112002

Other (OTH) AF: 0.00436 AC: 263 AN: 60390

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152260 Hom.: 34 Cov.: 32 AF XY: 0.00607 AC XY: 452 AN XY: 74444

African (AFR) AF: 0.000962 AC: 40 AN: 41562

American (AMR) AF: 0.0161 AC: 246 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0947 AC: 489 AN: 5162

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.189 Hom.: 9220

Bravo AF: 0.00852

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0141 AC: 1707

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.62
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.013	D
Vest4		0.17
MPC		0.44
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.24
gMVP		0.53
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79915936; hg19: chr19-30193653; COSMIC: COSV60364771; COSMIC: COSV60364771;