15-41810717-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chr15-41810717-CAAAAA-C
• rs58612719
• NM_014994.3:c.207-148_207-144delAAAAA

Variant summary

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

The NM_014994.3(MAPKBP1):​c.207-148_207-144delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 418,014 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 0)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: MAPKBP1 NM_014994.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.616
• 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 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0322) population. However there is too low homozygotes in high coverage region: (expected more than 56, got 0).

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.207-148_207-144delAAAAA		intron	N/A	NP_055809.2	O60336-6
	MAPKBP1	NM_001128608.2		c.207-148_207-144delAAAAA		intron	N/A	NP_001122080.1	O60336-1
	MAPKBP1	NM_001265611.2		c.207-148_207-144delAAAAA		intron	N/A	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.207-148_207-144delAAAAA		intron	N/A	ENSP00000397570.2	O60336-6
	MAPKBP1	ENST00000456763.6	TSL:1	c.207-148_207-144delAAAAA		intron	N/A	ENSP00000393099.2	O60336-1
	MAPKBP1	ENST00000514566.5	TSL:1	c.207-148_207-144delAAAAA		intron	N/A	ENSP00000426154.1	O60336-2

Frequencies

GnomAD3 genomes AF: 0.0000952 AC: 8 AN: 84076 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000484

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0291 AC: 9704 AN: 333950 Hom.: 0 AF XY: 0.0289 AC XY: 5090 AN XY: 175942

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0333 AC: 319 AN: 9580

American (AMR) AF: 0.0260 AC: 337 AN: 12952

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 292 AN: 10014

East Asian (EAS) AF: 0.0118 AC: 256 AN: 21770

South Asian (SAS) AF: 0.0338 AC: 1155 AN: 34128

European-Finnish (FIN) AF: 0.0270 AC: 665 AN: 24616

Middle Eastern (MID) AF: 0.0316 AC: 46 AN: 1454

European-Non Finnish (NFE) AF: 0.0303 AC: 6067 AN: 200364

Other (OTH) AF: 0.0297 AC: 567 AN: 19072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000952 AC: 8 AN: 84064 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 6 AN XY: 38872

African (AFR) AF: 0.000172 AC: 4 AN: 23312

American (AMR) AF: 0.00 AC: 0 AN: 7716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2220

East Asian (EAS) AF: 0.00 AC: 0 AN: 2684

South Asian (SAS) AF: 0.000844 AC: 2 AN: 2370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.0000484 AC: 2 AN: 41348

Other (OTH) AF: 0.00 AC: 0 AN: 1104

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58612719; hg19: chr15-42102915;