6-36138879-C-T

Variant names:

• chr6-36138879-C-T
• rs1052378549
• NM_002754.5:c.842C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002754.5(MAPK13):​c.842C>T​(p.Ala281Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A281G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAPK13 NM_002754.5 missense, splice_region
• Scores: Splicing: ADA: 0.9946
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10
• Publications: 0 publications found

Genes affected

MAPK13 (HGNC:6875): (mitogen-activated protein kinase 13) This gene encodes a member of the mitogen-activated protein (MAP) kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The encoded protein is a p38 MAP kinase and is activated by proinflammatory cytokines and cellular stress. Substrates of the encoded protein include the transcription factor ATF2 and the microtubule dynamics regulator stathmin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]

BRPF3-AS1 (HGNC:55591): (BRPF3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002754.5. 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
	MAPK13	NM_002754.5	MANE Select	c.842C>T	p.Ala281Val	missense splice_region	Exon 11 of 12	NP_002745.1	O15264-1
	MAPK13	NR_072996.2		n.760C>T		splice_region non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK13	ENST00000211287.9	TSL:1 MANE Select	c.842C>T	p.Ala281Val	missense splice_region	Exon 11 of 12	ENSP00000211287.4	O15264-1
	MAPK13	ENST00000373766.9	TSL:1	c.690C>T	p.Gly230Gly	splice_region synonymous	Exon 9 of 10	ENSP00000362871.5	O15264-2
	MAPK13	ENST00000874020.1		c.1055C>T	p.Ala352Val	missense splice_region	Exon 11 of 12	ENSP00000544079.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458038 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725176

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110168

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.82		Loss of disorder (P = 0.0686)
MVP		0.89
MPC		0.74
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.71
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.030		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: rs1052378549; hg19: chr6-36106656;