2-134986311-T-C

Position:

• chr2-134986311-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_025052.5(MAP3K19):​c.2561A>G​(p.Asp854Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MAP3K19 NM_025052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09789887).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K19	NM_025052.5	c.2561A>G	p.Asp854Gly	missense_variant	10/13	ENST00000392915.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K19	ENST00000392915.7	c.2561A>G	p.Asp854Gly	missense_variant	10/13	5	NM_025052.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461476 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.2561A>G (p.D854G) alteration is located in exon 7 (coding exon 7) of the MAP3K19 gene. This alteration results from a A to G substitution at nucleotide position 2561, causing the aspartic acid (D) at amino acid position 854 to be replaced by a glycine (G). 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	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0038	T;T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.54	.;T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.098	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	.;N;N;N;.
REVEL	Benign	0.089
Sift	Uncertain	0.0040	.;D;D;D;.
Sift4G	Uncertain	0.017	.;D;D;T;.
Polyphen		0.0	B;B;B;.;.
Vest4		0.13, 0.13
MutPred		0.16		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;.;.;
MVP		0.80
MPC		0.16
ClinPred		0.21	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.027

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-135743881;