19-7909883-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_145185.4(MAP2K7):c.253C>T(p.Arg85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,373,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: MAP2K7 NM_145185.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

MAP2K7 (HGNC:6847): (mitogen-activated protein kinase kinase 7) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2,MAP3K3/MEKK5, and MAP4K2/GCK. This kinase is involved in the signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3507526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K7	NM_145185.4	c.253C>T	p.Arg85Cys	missense_variant	2/11	ENST00000397979.4
MAP2K7	NM_001297555.2	c.301C>T	p.Arg101Cys	missense_variant	3/12
MAP2K7	NM_001297556.2	c.253C>T	p.Arg85Cys	missense_variant	2/11
MAP2K7	XM_006722800.3	c.301C>T	p.Arg101Cys	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K7	ENST00000397979.4	c.253C>T	p.Arg85Cys	missense_variant	2/11	1	NM_145185.4	P4
MAP2K7	ENST00000397983.7	c.301C>T	p.Arg101Cys	missense_variant	3/12	1		A1
MAP2K7	ENST00000397981.7	c.253C>T	p.Arg85Cys	missense_variant	2/11	1
MAP2K7	ENST00000468058.1	n.318C>T		non_coding_transcript_exon_variant	2/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000789 AC: 1 AN: 126774 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000991

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1373058 Hom.: 0 Cov.: 33 AF XY: 0.0000119 AC XY: 8 AN XY: 674802

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000656

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000845

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000195 AC: 1

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

Apr 17, 2023

The c.253C>T (p.R85C) alteration is located in exon 2 (coding exon 2) of the MAP2K7 gene. This alteration results from a C to T substitution at nucleotide position 253, causing the arginine (R) at amino acid position 85 to be replaced by a cysteine (C). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.22
MutPred		0.27		Gain of catalytic residue at P84 (P = 0.0134);.;Gain of catalytic residue at P84 (P = 0.0134);
MVP		0.65
MPC		1.5
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.33
gMVP		0.40

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: rs766635456; hg19: chr19-7974768;