chr1-15684609-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_015164.4(PLEKHM2):​c.51G>A​(p.Ser17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,303,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 synonymous

Scores

1
1

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0360
Variant links:
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
Variant 1-15684609-G-A is Benign according to our data. Variant chr1-15684609-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 772520.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.036 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLEKHM2NM_015164.4 linkuse as main transcriptc.51G>A p.Ser17= synonymous_variant 1/20 ENST00000375799.8 NP_055979.2
PLEKHM2NM_001410755.1 linkuse as main transcriptc.51G>A p.Ser17= synonymous_variant 1/19 NP_001397684.1
PLEKHM2XM_017000757.1 linkuse as main transcriptc.99+2910G>A intron_variant XP_016856246.1
PLEKHM2XM_017000758.1 linkuse as main transcriptc.99+2910G>A intron_variant XP_016856247.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHM2ENST00000375799.8 linkuse as main transcriptc.51G>A p.Ser17= synonymous_variant 1/201 NM_015164.4 ENSP00000364956 P2Q8IWE5-1
PLEKHM2ENST00000375793.2 linkuse as main transcriptc.51G>A p.Ser17= synonymous_variant 1/195 ENSP00000364950 A2Q8IWE5-2
PLEKHM2ENST00000642363.1 linkuse as main transcriptc.51G>A p.Ser17= synonymous_variant 1/21 ENSP00000494591 A2
PLEKHM2ENST00000462455.1 linkuse as main transcriptn.69G>A non_coding_transcript_exon_variant 1/55

Frequencies

GnomAD3 genomes
AF:
0.0000665
AC:
10
AN:
150372
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000145
AC:
167
AN:
1152744
Hom.:
0
Cov.:
29
AF XY:
0.000144
AC XY:
81
AN XY:
561272
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000391
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000170
Gnomad4 OTH exome
AF:
0.000114
GnomAD4 genome
AF:
0.0000665
AC:
10
AN:
150372
Hom.:
0
Cov.:
30
AF XY:
0.0000409
AC XY:
3
AN XY:
73430
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000642

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
CADD
Benign
15
DANN
Uncertain
0.99
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370753597; hg19: chr1-16011104; API