22-50603940-C-G

Variant summary

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

The NM_012324.6(MAPK8IP2):c.641C>G(p.Pro214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,543,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: MAPK8IP2 NM_012324.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12683088).
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8IP2	NM_012324.6	c.641C>G	p.Pro214Arg	missense_variant	5/12	ENST00000329492.6
MAPK8IP2	XM_011530679.3	c.644C>G	p.Pro215Arg	missense_variant	5/12
MAPK8IP2	XM_011530680.3	c.542-12C>G		splice_polypyrimidine_tract_variant, intron_variant
MAPK8IP2	XM_011530681.3	c.542-33C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8IP2	ENST00000329492.6	c.641C>G	p.Pro214Arg	missense_variant	5/12	1	NM_012324.6	P1
MAPK8IP2	ENST00000008876.7	n.560C>G		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000941 AC: 13 AN: 138094 Hom.: 0 AF XY: 0.0000526 AC XY: 4 AN XY: 76038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

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: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 119 AN: 1391026 Hom.: 0 Cov.: 34 AF XY: 0.0000684 AC XY: 47 AN XY: 686902

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000990

Gnomad4 OTH exome AF: 0.0000690

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74476

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000597 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00000959 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jun 11, 2021

The c.641C>G (p.P214R) alteration is located in exon 5 (coding exon 5) of the MAPK8IP2 gene. This alteration results from a C to G substitution at nucleotide position 641, causing the proline (P) at amino acid position 214 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.90
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.058
Sift	Benign	0.12	T
Sift4G	Benign	0.59	T
Polyphen		0.43	B
Vest4		0.13
MutPred		0.24		Loss of catalytic residue at P214 (P = 0.0036);
MVP		0.38
ClinPred		0.036	T
GERP RS		2.5
Varity_R		0.027
gMVP		0.20

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: rs761368512; hg19: chr22-51042369;