chr11-64796285-C-T

Position:

• chr11-64796285-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004579.5(MAP4K2):​c.1739G>A​(p.Arg580His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,531,454 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (60 hom.)
• Consequence: MAP4K2 NM_004579.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.57

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]

MAP4K2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010477126).
• BP6: Variant 11-64796285-C-T is Benign according to our data. Variant chr11-64796285-C-T is described in ClinVar as [Benign]. Clinvar id is 776623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1811/152274) while in subpopulation AFR AF= 0.0225 (934/41566). AF 95% confidence interval is 0.0213. There are 17 homozygotes in gnomad4. There are 877 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K2	NM_004579.5	c.1739G>A	p.Arg580His	missense_variant	24/32	ENST00000294066.7	NP_004570.2
MAP4K2	NM_001307990.2	c.1715G>A	p.Arg572His	missense_variant	24/32		NP_001294919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K2	ENST00000294066.7	c.1739G>A	p.Arg580His	missense_variant	24/32	1	NM_004579.5	ENSP00000294066.2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1812 AN: 152156 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00819 AC: 1521 AN: 185614 Hom.: 12 AF XY: 0.00847 AC XY: 827 AN XY: 97692

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00757

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.0000610

Gnomad SAS exome AF: 0.00498

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.00892

GnomAD4 exome AF: 0.00696 AC: 9602 AN: 1379180 Hom.: 60 Cov.: 32 AF XY: 0.00702 AC XY: 4753 AN XY: 677092

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.00886

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00579

Gnomad4 FIN exome AF: 0.00166

Gnomad4 NFE exome AF: 0.00655

Gnomad4 OTH exome AF: 0.00913

GnomAD4 genome AF: 0.0119 AC: 1811 AN: 152274 Hom.: 17 Cov.: 32 AF XY: 0.0118 AC XY: 877 AN XY: 74454

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00704 Hom.: 2

Bravo AF: 0.0135

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00788 AC: 931

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.39
MVP		0.73
MPC		1.1
ClinPred		0.030	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34264803; hg19: chr11-64563757;