chr1-15684510-GGGCGGC-G

Variant names:

• chr1-15684510-GGGCGGC-G
• rs767880122
• NM_015164.4:c.-40_-35delCGGCGG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015164.4(PLEKHM2):​c.-40_-35delCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 832,692 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000084 (1 hom.)
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20

Genes affected

PLEKHM2 (HGNC:29131): (pleckstrin homology and RUN domain containing M2) This gene encodes a protein that binds the plus-end directed microtubule motor protein kinesin, together with the lysosomal GTPase Arl8, and is required for lysosomes to distribute away from the microtubule-organizing center. The encoded protein belongs to the multisubunit BLOC-one-related complex that regulates lysosome positioning. It binds a Salmonella effector protein called Salmonella induced filament A and is a critical host determinant in Salmonella pathogenesis. It has a domain architecture consisting of an N-terminal RPIP8, UNC-14, and NESCA (RUN) domain that binds kinesin-1 as well as the lysosomal GTPase Arl8, and a C-terminal pleckstrin homology domain that binds the Salmonella induced filament A effector protein. Naturally occurring mutations in this gene lead to abnormal localization of lysosomes, impaired autophagy flux and are associated with recessive dilated cardiomyopathy and left ventricular noncompaction. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.-40_-35delCGGCGG		5_prime_UTR_variant	Exon 1 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.-40_-35delCGGCGG		5_prime_UTR_variant	Exon 1 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.99+2820_99+2825delCGGCGG		intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1	c.99+2820_99+2825delCGGCGG		intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799	c.-40_-35delCGGCGG		5_prime_UTR_variant	Exon 1 of 20	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793	c.-40_-35delCGGCGG		5_prime_UTR_variant	Exon 1 of 19	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.-48_-43delGGCGGC		upstream_gene_variant				ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.-30_-25delGGCGGC		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000841 AC: 7 AN: 832692 Hom.: 1 AF XY: 0.00000768 AC XY: 3 AN XY: 390524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000953

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs767880122; hg19: chr1-16011005;