6-136792541-C-CCGCCG

Variant names:

• chr6-136792541-C-CCGCCG
• rs5880308
• NM_001438058.1:c.96+99_96+103dupCGGCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001438058.1(MAP3K5):​c.96+99_96+103dupCGGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 0)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: MAP3K5 NM_001438058.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 2 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00322 (480/149090) while in subpopulation EAS AF = 0.0193 (95/4910). AF 95% confidence interval is 0.0162. There are 2 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 480 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438058.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	NM_001438058.1		c.96+99_96+103dupCGGCG		intron	N/A	NP_001424987.1
	MAP3K5	NM_005923.4	MANE Select	c.-389_-385dupCGGCG		upstream_gene	N/A	NP_005914.1
	MAP3K5	NM_001438579.1		c.-831_-827dupCGGCG		upstream_gene	N/A	NP_001425508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000698928.1		c.96+103_96+104insCGGCG		intron	N/A	ENSP00000514039.1
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.-385_-384insCGGCG		upstream_gene	N/A	ENSP00000351908.4
	MAP3K5	ENST00000954598.1		c.-385_-384insCGGCG		upstream_gene	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 477 AN: 148980 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00378

Gnomad ASJ AF: 0.0247

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.00418

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00391

GnomAD4 exome AF: 0.0000619 AC: 1 AN: 16164 Hom.: 0 Cov.: 0 AF XY: 0.000126 AC XY: 1 AN XY: 7930

African (AFR) AF: 0.00 AC: 0 AN: 266

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 90

East Asian (EAS) AF: 0.00 AC: 0 AN: 96

South Asian (SAS) AF: 0.00 AC: 0 AN: 492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 42

European-Non Finnish (NFE) AF: 0.0000684 AC: 1 AN: 14610

Other (OTH) AF: 0.00 AC: 0 AN: 538

GnomAD4 genome AF: 0.00322 AC: 480 AN: 149090 Hom.: 2 Cov.: 0 AF XY: 0.00362 AC XY: 263 AN XY: 72712

African (AFR) AF: 0.00150 AC: 61 AN: 40736

American (AMR) AF: 0.00377 AC: 57 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 85 AN: 3446

East Asian (EAS) AF: 0.0193 AC: 95 AN: 4910

South Asian (SAS) AF: 0.00419 AC: 20 AN: 4778

European-Finnish (FIN) AF: 0.00161 AC: 16 AN: 9928

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00205 AC: 137 AN: 66932

Other (OTH) AF: 0.00386 AC: 8 AN: 2070

Alfa AF: 0.00158 Hom.: 806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5880308; hg19: chr6-137113679;