22-50600850-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012324.6(MAPK8IP2):c.32C>T(p.Ser11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000977 in 1,310,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MAPK8IP2 NM_012324.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

Genes affected

MAPK8IP2 (HGNC:6883): (mitogen-activated protein kinase 8 interacting protein 2) This gene encodes a scaffold protein that is thought to be involved in the regulation of the c-Jun amino-terminal kinase signaling pathway. This protein has been shown to interact with and regulate the activity of MAPK8/JNK1 and MAP2K7/MKK7 kinases. [provided by RefSeq, Jun 2017]

CHKB (HGNC:1938): (choline kinase beta) Choline kinase (CK) and ethanolamine kinase (EK) catalyze the phosphorylation of choline/ethanolamine to phosphocholine/phosphoethanolamine. This is the first enzyme in the biosynthesis of phosphatidylcholine/phosphatidylethanolamine in all animal cells. The highly purified CKs from mammalian sources and their recombinant gene products have been shown to have EK activity also, indicating that both activities reside on the same protein. The choline kinase-like protein encoded by CHKL belongs to the choline/ethanolamine kinase family; however, its exact function is not known. Read-through transcripts are expressed from this locus that include exons from the downstream CPT1B locus. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22861004).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8IP2	NM_012324.6	c.32C>T	p.Ser11Phe	missense_variant	1/12	ENST00000329492.6
MAPK8IP2	XM_011530679.3	c.32C>T	p.Ser11Phe	missense_variant	1/12
MAPK8IP2	XM_011530680.3	c.32C>T	p.Ser11Phe	missense_variant	1/12
MAPK8IP2	XM_011530681.3	c.32C>T	p.Ser11Phe	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8IP2	ENST00000329492.6	c.32C>T	p.Ser11Phe	missense_variant	1/12	1	NM_012324.6	P1
CHKB	ENST00000463053.1	n.306+300G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000742 AC: 11 AN: 148238 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000105

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000725 AC: 9 AN: 124060 Hom.: 0 AF XY: 0.0000143 AC XY: 1 AN XY: 70158

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.0000536

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 117 AN: 1162324 Hom.: 0 Cov.: 29 AF XY: 0.0000974 AC XY: 56 AN XY: 574956

Gnomad4 AFR exome AF: 0.0000452

Gnomad4 AMR exome AF: 0.0000828

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000293

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000477

GnomAD4 genome AF: 0.0000742 AC: 11 AN: 148346 Hom.: 0 Cov.: 29 AF XY: 0.0000692 AC XY: 5 AN XY: 72300

Gnomad4 AFR AF: 0.0000972

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000446 AC: 5

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

May 24, 2023

The c.32C>T (p.S11F) alteration is located in exon 1 (coding exon 1) of the MAPK8IP2 gene. This alteration results from a C to T substitution at nucleotide position 32, causing the serine (S) at amino acid position 11 to be replaced by a phenylalanine (F). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.88	D;D;N;N
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.95	P
Vest4		0.13
MVP		0.63
ClinPred		0.099	T
GERP RS		3.0
Varity_R		0.19
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs554703703; hg19: chr22-51039279;