rs493573

Variant names:

• chr11-64789582-C-T
• rs493573
• NM_004579.5:c.2418G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004579.5(MAP4K2):​c.2418G>A​(p.Ala806Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,603,730 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (12 hom.)
• Consequence: MAP4K2 NM_004579.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.80
• Publications: 15 publications found

Genes affected

MAP4K2 (HGNC:6864): (mitogen-activated protein kinase kinase kinase kinase 2) The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-64789582-C-T is Benign according to our data. Variant chr11-64789582-C-T is described in ClinVar as [Benign]. Clinvar id is 720714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00638 (971/152228) while in subpopulation AFR AF = 0.0226 (937/41532). AF 95% confidence interval is 0.0214. There are 14 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K2	NM_004579.5	c.2418G>A	p.Ala806Ala	synonymous_variant	Exon 32 of 32	ENST00000294066.7	NP_004570.2
MAP4K2	NM_001307990.2	c.2394G>A	p.Ala798Ala	synonymous_variant	Exon 32 of 32		NP_001294919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K2	ENST00000294066.7	c.2418G>A	p.Ala806Ala	synonymous_variant	Exon 32 of 32	1	NM_004579.5	ENSP00000294066.2

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 967 AN: 152110 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00163 AC: 378 AN: 231890 AF XY: 0.00106

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.000992

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000503

Gnomad NFE exome AF: 0.0000576

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.000618 AC: 897 AN: 1451502 Hom.: 12 Cov.: 31 AF XY: 0.000530 AC XY: 382 AN XY: 720842

African (AFR) AF: 0.0217 AC: 723 AN: 33378

American (AMR) AF: 0.00107 AC: 46 AN: 42844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.0000949 AC: 8 AN: 84320

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52804

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5756

European-Non Finnish (NFE) AF: 0.0000307 AC: 34 AN: 1107078

Other (OTH) AF: 0.00131 AC: 79 AN: 60078

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152228 Hom.: 14 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74420

African (AFR) AF: 0.0226 AC: 937 AN: 41532

American (AMR) AF: 0.00150 AC: 23 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00223 Hom.: 10

Bravo AF: 0.00689

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs493573; hg19: chr11-64557054;