dbSNP rs372403777: MLKL:p.Glu418Gln (chr16-74675089-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152649.4(MLKL):c.1252G>C(p.Glu418Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MLKL
NM_152649.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.430

Variant links:

Genes affected

MLKL (HGNC:26617): (mixed lineage kinase domain like pseudokinase) This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis. High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]

MLKL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05996543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4 link	c.1252G>C	p.Glu418Gln	missense_variant	Exon 10 of 11	ENST00000308807.12	NP_689862.1	Q8NB16-1
MLKL	NM_001142497.3 link	c.628G>C	p.Glu210Gln	missense_variant	Exon 5 of 6		NP_001135969.1	Q8NB16-2
MLKL	XM_005255834.5 link	c.1252G>C	p.Glu418Gln	missense_variant	Exon 11 of 12		XP_005255891.1	Q8NB16-1
MLKL	XM_047433704.1 link	c.*5G>C		3_prime_UTR_variant	Exon 10 of 10		XP_047289660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12 link	c.1252G>C	p.Glu418Gln	missense_variant	Exon 10 of 11	2	NM_152649.4	ENSP00000308351.7		Q8NB16-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250904

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727196

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.17

DANN

Benign

0.15

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.35

T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.61

.;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.023

Sift

Benign

0.70

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.24

B;B

Vest4

0.12

MutPred

0.43

.;Gain of MoRF binding (P = 0.0365);

MVP

0.45

MPC

0.019

ClinPred

0.046

GERP RS

-6.7

Varity_R

0.086

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over