15-41810717-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

• chr15-41810717-CAAA-C
• rs58612719
• NM_014994.3:c.207-146_207-144delAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014994.3(MAPKBP1):​c.207-146_207-144delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 421,580 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0066 (3 hom., cov: 0)
  • Exomes 𝑓: 0.17 (6 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00657 (552/84062) while in subpopulation EAS AF = 0.0403 (108/2678). AF 95% confidence interval is 0.0342. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.207-146_207-144delAAA		intron	N/A	NP_055809.2	O60336-6
	MAPKBP1	NM_001128608.2		c.207-146_207-144delAAA		intron	N/A	NP_001122080.1	O60336-1
	MAPKBP1	NM_001265611.2		c.207-146_207-144delAAA		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.207-146_207-144delAAA		intron	N/A	ENSP00000397570.2	O60336-6
	MAPKBP1	ENST00000456763.6	TSL:1	c.207-146_207-144delAAA		intron	N/A	ENSP00000393099.2	O60336-1
	MAPKBP1	ENST00000514566.5	TSL:1	c.207-146_207-144delAAA		intron	N/A	ENSP00000426154.1	O60336-2

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 553 AN: 84074 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00195

Gnomad ASJ AF: 0.00495

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.00543

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00639

GnomAD4 exome AF: 0.175 AC: 58903 AN: 337518 Hom.: 6 AF XY: 0.175 AC XY: 31169 AN XY: 177950

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

African (AFR) AF: 0.145 AC: 1387 AN: 9558

American (AMR) AF: 0.166 AC: 2164 AN: 13034

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 1817 AN: 10090

East Asian (EAS) AF: 0.0920 AC: 1956 AN: 21256

South Asian (SAS) AF: 0.183 AC: 6351 AN: 34678

European-Finnish (FIN) AF: 0.176 AC: 4395 AN: 24982

Middle Eastern (MID) AF: 0.188 AC: 277 AN: 1472

European-Non Finnish (NFE) AF: 0.183 AC: 37187 AN: 203182

Other (OTH) AF: 0.175 AC: 3369 AN: 19266

⚠️ 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: 0.00657 AC: 552 AN: 84062 Hom.: 3 Cov.: 0 AF XY: 0.00723 AC XY: 281 AN XY: 38862

African (AFR) AF: 0.0118 AC: 276 AN: 23312

American (AMR) AF: 0.00194 AC: 15 AN: 7714

Ashkenazi Jewish (ASJ) AF: 0.00495 AC: 11 AN: 2222

East Asian (EAS) AF: 0.0403 AC: 108 AN: 2678

South Asian (SAS) AF: 0.00549 AC: 13 AN: 2370

European-Finnish (FIN) AF: 0.00152 AC: 4 AN: 2628

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

European-Non Finnish (NFE) AF: 0.00285 AC: 118 AN: 41350

Other (OTH) AF: 0.00634 AC: 7 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

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

dbSNP: rs58612719; hg19: chr15-42102915;