rs79915936

chr19-29702746-T-Cchr19-29702746-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_031448.6(C19orf12):c.392A>G(p.Lys131Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K131E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C19orf12 NM_031448.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.624

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 Uncertain_significance. Variant got 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0737997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.392A>G	p.Lys131Arg	missense_variant	3/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14	c.392A>G	p.Lys131Arg	missense_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D;D;.;.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	0.93	D;D;D;D
Sift4G	Benign	0.29	T;T;T;T;T
Vest4		0.074
MVP		0.22
MPC		0.29
ClinPred		0.13	T
GERP RS		2.0
Varity_R		0.097
gMVP		0.35

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: rs79915936; hg19: chr19-30193653;