2-134981155-G-A

Variant names:

• chr2-134981155-G-A
• rs1312783726
• NM_025052.5:c.3586C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025052.5(MAP3K19):​c.3586C>T​(p.Pro1196Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K19 NM_025052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75

Genes affected

MAP3K19 (HGNC:26249): (mitogen-activated protein kinase kinase kinase 19) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K19	NM_025052.5	c.3586C>T	p.Pro1196Ser	missense_variant	Exon 12 of 13	ENST00000392915.7	NP_079328.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K19	ENST00000392915.7	c.3586C>T	p.Pro1196Ser	missense_variant	Exon 12 of 13	5	NM_025052.5	ENSP00000376647.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3586C>T (p.P1196S) alteration is located in exon 9 (coding exon 9) of the MAP3K19 gene. This alteration results from a C to T substitution at nucleotide position 3586, causing the proline (P) at amino acid position 1196 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-1.1	N;N;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	.;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.046	.;D;T;T;T;T;T
Sift4G	Uncertain	0.053	.;T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;D;D;.
Vest4		0.61, 0.77, 0.55, 0.79, 0.79
MutPred		0.36		Gain of catalytic residue at P1196 (P = 0.0769);Gain of catalytic residue at P1196 (P = 0.0769);.;.;.;.;.;
MVP		0.73
MPC		0.54
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.33
gMVP		0.48

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: rs1312783726; hg19: chr2-135738725; COSMIC: COSV59640795; COSMIC: COSV59640795;