chr15-41775365-C-A

Variant names:

• chr15-41775365-C-A
• NM_014994.3:c.90C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014994.3(MAPKBP1):​c.90C>A​(p.Asn30Lys) 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 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAPKBP1 NM_014994.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

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]

MAPKBP1 Gene-Disease associations (from GenCC):

• nephronophthisis 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• late-onset nephronophthisis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13810474).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKBP1	NM_014994.3	MANE Select	c.90C>A	p.Asn30Lys	missense	Exon 2 of 31	NP_055809.2	O60336-6
	MAPKBP1	NM_001128608.2		c.90C>A	p.Asn30Lys	missense	Exon 2 of 32	NP_001122080.1	O60336-1
	MAPKBP1	NM_001265611.2		c.90C>A	p.Asn30Lys	missense	Exon 2 of 30	NP_001252540.1	O60336-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKBP1	ENST00000457542.7	TSL:1 MANE Select	c.90C>A	p.Asn30Lys	missense	Exon 2 of 31	ENSP00000397570.2	O60336-6
	MAPKBP1	ENST00000456763.6	TSL:1	c.90C>A	p.Asn30Lys	missense	Exon 2 of 32	ENSP00000393099.2	O60336-1
	MAPKBP1	ENST00000514566.5	TSL:1	c.90C>A	p.Asn30Lys	missense	Exon 2 of 30	ENSP00000426154.1	O60336-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.0080	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.032
Sift	Benign	0.37	T
Sift4G	Benign	0.42	T
Polyphen		0.043	B
Vest4		0.17
MutPred		0.45		Gain of methylation at N30 (P = 0.0176)
MVP		0.34
MPC		0.84
ClinPred		0.21	T
GERP RS		4.3
PromoterAI		-0.075	Neutral
Varity_R		0.14
gMVP		0.66

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

Other links and lift over

hg19: chr15-42067563;