1-15719829-C-T
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_015164.4(PLEKHM2):c.561C>T(p.His187His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,613,820 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0043 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0056 ( 48 hom. )
Consequence
PLEKHM2
NM_015164.4 synonymous
NM_015164.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.91
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
Variant 1-15719829-C-T is Benign according to our data. Variant chr1-15719829-C-T is described in ClinVar as [Benign]. Clinvar id is 478101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-3.91 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0056 (8186/1461530) while in subpopulation MID AF= 0.0232 (134/5768). AF 95% confidence interval is 0.02. There are 48 homozygotes in gnomad4_exome. There are 4024 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLEKHM2 | NM_015164.4 | c.561C>T | p.His187His | synonymous_variant | 6/20 | ENST00000375799.8 | NP_055979.2 | |
PLEKHM2 | NM_001410755.1 | c.561C>T | p.His187His | synonymous_variant | 6/19 | NP_001397684.1 | ||
PLEKHM2 | XM_017000757.1 | c.600C>T | p.His200His | synonymous_variant | 6/20 | XP_016856246.1 | ||
PLEKHM2 | XM_017000758.1 | c.600C>T | p.His200His | synonymous_variant | 6/19 | XP_016856247.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEKHM2 | ENST00000375799.8 | c.561C>T | p.His187His | synonymous_variant | 6/20 | 1 | NM_015164.4 | ENSP00000364956.3 | ||
PLEKHM2 | ENST00000375793.2 | c.561C>T | p.His187His | synonymous_variant | 6/19 | 5 | ENSP00000364950.2 | |||
PLEKHM2 | ENST00000642363.1 | c.561C>T | p.His187His | synonymous_variant | 6/21 | ENSP00000494591.1 | ||||
PLEKHM2 | ENST00000462455.1 | n.469C>T | non_coding_transcript_exon_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00430 AC: 654AN: 152172Hom.: 5 Cov.: 31
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GnomAD3 exomes AF: 0.00455 AC: 1134AN: 249198Hom.: 8 AF XY: 0.00448 AC XY: 605AN XY: 135188
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GnomAD4 exome AF: 0.00560 AC: 8186AN: 1461530Hom.: 48 Cov.: 31 AF XY: 0.00553 AC XY: 4024AN XY: 727052
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GnomAD4 genome AF: 0.00429 AC: 654AN: 152290Hom.: 5 Cov.: 31 AF XY: 0.00414 AC XY: 308AN XY: 74480
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dilated Cardiomyopathy, Recessive Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at