2-101827359-C-G

Variant names:

• chr2-101827359-C-G
• rs2236936
• NM_001395002.1:c.417+1930C>G

Variant summary

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

The NM_001395002.1(MAP4K4):​c.417+1930C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 152,046 control chromosomes in the GnomAD database, including 43,579 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 0.75 (43579 hom., cov: 31)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 6 publications found

Genes affected

MAP4K4 (HGNC:6866): (mitogen-activated protein kinase kinase kinase kinase 4) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MAP4K4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

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 (AFR) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395002.1. 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
	MAP4K4	NM_001395002.1	MANE Select	c.417+1930C>G		intron	N/A	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.417+1930C>G		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.417+1930C>G		intron	N/A	NP_001371421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.417+1930C>G		intron	N/A	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.417+1930C>G		intron	N/A	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.417+1930C>G		intron	N/A	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114399 AN: 151928 Hom.: 43523 Cov.: 31

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.726

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

GnomAD4 genome AF: 0.753 AC: 114510 AN: 152046 Hom.: 43579 Cov.: 31 AF XY: 0.755 AC XY: 56109 AN XY: 74304

African (AFR) AF: 0.879 AC: 36483 AN: 41498

American (AMR) AF: 0.716 AC: 10934 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2326 AN: 3472

East Asian (EAS) AF: 0.767 AC: 3956 AN: 5156

South Asian (SAS) AF: 0.700 AC: 3371 AN: 4818

European-Finnish (FIN) AF: 0.747 AC: 7877 AN: 10540

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 47214 AN: 67978

Other (OTH) AF: 0.729 AC: 1542 AN: 2116

Alfa AF: 0.635 Hom.: 1774

Bravo AF: 0.756

Asia WGS AF: 0.787 AC: 2736 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	1.4
DANN	Benign	0.58
PhyloP100		-0.33
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: rs2236936; hg19: chr2-102443821;