16-74682691-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152649.4(MLKL):​c.916C>G​(p.Arg306Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.916C>G	p.Arg306Gly	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>G	p.Arg306Gly	missense_variant	Exon 6 of 11	2	NM_152649.4	ENSP00000308351.7
MLKL	ENST00000306247.11	c.536-7287C>G		intron_variant	Intron 3 of 5	1		ENSP00000303118.7
MLKL	ENST00000571303.1	n.385C>G		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000461110.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.68
MutPred		0.69		Loss of methylation at R306 (P = 0.0143);
MVP		0.89
MPC		0.15
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.73
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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;