rs2237269

Variant names:

• chr6-136645481-G-C
• rs2237269
• NM_005923.4:c.1789-2912C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005923.4(MAP3K5):​c.1789-2912C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 151,976 control chromosomes in the GnomAD database, including 4,370 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4370 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.161
• Publications: 1 publications found

Genes affected

MAP3K5 (HGNC:6857): (mitogen-activated protein kinase kinase kinase 5) Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

MAP3K5-AS1 (HGNC:40358): (MAP3K5 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005923.4. 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
	MAP3K5	NM_005923.4	MANE Select	c.1789-2912C>G		intron	N/A	NP_005914.1	Q99683-1
	MAP3K5	NM_001438058.1		c.2116-2912C>G		intron	N/A	NP_001424987.1	A0A8V8TMH5
	MAP3K5	NM_001438579.1		c.1207-2912C>G		intron	N/A	NP_001425508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.1789-2912C>G		intron	N/A	ENSP00000351908.4	Q99683-1
	MAP3K5	ENST00000698928.1		c.2116-2912C>G		intron	N/A	ENSP00000514039.1	A0A8V8TMH5
	MAP3K5	ENST00000954598.1		c.1858-2912C>G		intron	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33726 AN: 151858 Hom.: 4353 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.222 AC: 33769 AN: 151976 Hom.: 4370 Cov.: 32 AF XY: 0.221 AC XY: 16433 AN XY: 74278

African (AFR) AF: 0.346 AC: 14340 AN: 41416

American (AMR) AF: 0.211 AC: 3216 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 418 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2003 AN: 5150

South Asian (SAS) AF: 0.220 AC: 1062 AN: 4818

European-Finnish (FIN) AF: 0.135 AC: 1428 AN: 10578

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10687 AN: 67970

Other (OTH) AF: 0.200 AC: 421 AN: 2104

Alfa AF: 0.197 Hom.: 419

Bravo AF: 0.231

Asia WGS AF: 0.267 AC: 926 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.39
PhyloP100		0.16
Mutation Taster		=100/0	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: rs2237269; hg19: chr6-136966619;