NM_031448.6:c.392A>C

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

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

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

Sel.	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	Q9NSK7-4
	C19orf12	NM_001031726.4		c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	NP_001026896.3	Q9NSK7-4
	C19orf12	NM_001256047.2		c.392A>C	p.Lys131Thr	missense	Exon 3 of 3	NP_001242976.1	Q9NSK7-4

Ensembl Transcripts

Sel.	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	Q9NSK7-4
	C19orf12	ENST00000392276.1	TSL:1	c.200A>C	p.Lys67Thr	missense	Exon 2 of 2	ENSP00000376102.1	Q9NSK7-2
	C19orf12	ENST00000592153.5	TSL:1	c.*13A>C		3_prime_UTR	Exon 4 of 4	ENSP00000467117.1	Q9NSK7-3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 43 (1)
-	-	1	Neurodegeneration with brain iron accumulation 4 (1)
-	-	1	not provided (1)

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;