15-41775372-G-C

Position:

• chr15-41775372-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014994.3(MAPKBP1):​c.97G>C​(p.Glu33Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPKBP1 NM_014994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73

Genes affected

MAPKBP1 (HGNC:29536): (mitogen-activated protein kinase binding protein 1) This gene encodes a scaffold protein that regulates the JNK (c-Jun N-terminal kinase) and NOD2 (nucleotide-binding oligomerization domain-containing protein 2) signaling pathways. The encoded protein interacts with another related JNK pathway scaffold protein, WDR62, via a conserved dimerization domain, and enhances JNK signaling. This protein may play a role in bacterial immunity by binding to the NOD2 receptor and negatively regulating downstream antibacterial and pro-inflammatory signaling. Mutations in this gene that impair cellular localization of the encoded protein cause a form of nephronophthisis, an autosomal-recessive kidney disorder, in human patients. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MAPKBP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.28534827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPKBP1	NM_014994.3	c.97G>C	p.Glu33Gln	missense_variant	2/31	ENST00000457542.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPKBP1	ENST00000457542.7	c.97G>C	p.Glu33Gln	missense_variant	2/31	1	NM_014994.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 25, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M;M;M;.;.
MutationTaster	Benign	0.78	D;D;D;D;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.063	T;T;T;T;.
Sift4G	Pathogenic	0.0	D;D;T;T;D
Polyphen		0.98	D;D;D;.;.
Vest4		0.30
MutPred		0.32		Gain of MoRF binding (P = 0.0405);Gain of MoRF binding (P = 0.0405);Gain of MoRF binding (P = 0.0405);Gain of MoRF binding (P = 0.0405);Gain of MoRF binding (P = 0.0405);
MVP		0.52
MPC		1.5
ClinPred		0.89	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.72

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: rs2064079900; hg19: chr15-42067570;