chr11-64792080-A-G

Position:

• chr11-64792080-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004579.5(MAP4K2):​c.1921T>C​(p.Ser641Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,434,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP4K2 NM_004579.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K2	NM_004579.5	c.1921T>C	p.Ser641Pro	missense_variant	27/32	ENST00000294066.7	NP_004570.2
MAP4K2	NM_001307990.2	c.1897T>C	p.Ser633Pro	missense_variant	27/32		NP_001294919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K2	ENST00000294066.7	c.1921T>C	p.Ser641Pro	missense_variant	27/32	1	NM_004579.5	ENSP00000294066.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1434086 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 710972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.1921T>C (p.S641P) alteration is located in exon 27 (coding exon 27) of the MAP4K2 gene. This alteration results from a T to C substitution at nucleotide position 1921, causing the serine (S) at amino acid position 641 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0092	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.082
Sift	Benign	0.040	D;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	B;.
Vest4		0.52
MutPred		0.79		Gain of glycosylation at S641 (P = 0.0329);.;
MVP		0.35
MPC		0.36
ClinPred		0.47	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64559552;