NM_152649.4:c.916C>T

Variant names:

• chr16-74682691-G-A
• rs145371410
• NM_152649.4:c.916C>T

Variant summary

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

The NM_152649.4(MLKL):​c.916C>T​(p.Arg306Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

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 rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.916C>T	p.Arg306Cys	missense_variant	Exon 6 of 11	ENST00000308807.12	NP_689862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.916C>T	p.Arg306Cys	missense_variant	Exon 6 of 11	2	NM_152649.4	ENSP00000308351.7
MLKL	ENST00000306247.11	c.536-7287C>T		intron_variant	Intron 3 of 5	1		ENSP00000303118.7
MLKL	ENST00000571303.1	n.385C>T		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000461110.1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000662

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251468 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135908

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000614 AC: 897 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.000584 AC XY: 425 AN XY: 727242

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 28 AN XY: 74412

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.916C>T (p.R306C) alteration is located in exon 6 (coding exon 5) of the MLKL gene. This alteration results from a C to T substitution at nucleotide position 916, causing the arginine (R) at amino acid position 306 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.74	P
Vest4		0.54
MVP		0.89
MPC		0.065
ClinPred		0.16	T
GERP RS		3.7
Varity_R		0.64
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs145371410; hg19: chr16-74716589;