1-15719829-C-T

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.91
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]

Genome browser will be placed here

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
PLEKHM2NM_015164.4 linkuse as main transcriptc.561C>T p.His187His synonymous_variant 6/20 ENST00000375799.8 NP_055979.2
PLEKHM2NM_001410755.1 linkuse as main transcriptc.561C>T p.His187His synonymous_variant 6/19 NP_001397684.1
PLEKHM2XM_017000757.1 linkuse as main transcriptc.600C>T p.His200His synonymous_variant 6/20 XP_016856246.1
PLEKHM2XM_017000758.1 linkuse as main transcriptc.600C>T p.His200His synonymous_variant 6/19 XP_016856247.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHM2ENST00000375799.8 linkuse as main transcriptc.561C>T p.His187His synonymous_variant 6/201 NM_015164.4 ENSP00000364956.3 Q8IWE5-1
PLEKHM2ENST00000375793.2 linkuse as main transcriptc.561C>T p.His187His synonymous_variant 6/195 ENSP00000364950.2 Q8IWE5-2
PLEKHM2ENST00000642363.1 linkuse as main transcriptc.561C>T p.His187His synonymous_variant 6/21 ENSP00000494591.1 A0A2R8Y575
PLEKHM2ENST00000462455.1 linkuse as main transcriptn.469C>T non_coding_transcript_exon_variant 5/55

Frequencies

GnomAD3 genomes
AF:
0.00430
AC:
654
AN:
152172
Hom.:
5
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00145
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00498
Gnomad ASJ
AF:
0.0173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00122
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.00623
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00455
AC:
1134
AN:
249198
Hom.:
8
AF XY:
0.00448
AC XY:
605
AN XY:
135188
show subpopulations
Gnomad AFR exome
AF:
0.00116
Gnomad AMR exome
AF:
0.00267
Gnomad ASJ exome
AF:
0.0156
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.000785
Gnomad FIN exome
AF:
0.000464
Gnomad NFE exome
AF:
0.00694
Gnomad OTH exome
AF:
0.00777
GnomAD4 exome
AF:
0.00560
AC:
8186
AN:
1461530
Hom.:
48
Cov.:
31
AF XY:
0.00553
AC XY:
4024
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.00134
Gnomad4 AMR exome
AF:
0.00304
Gnomad4 ASJ exome
AF:
0.0161
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.000805
Gnomad4 NFE exome
AF:
0.00630
Gnomad4 OTH exome
AF:
0.00510
GnomAD4 genome
AF:
0.00429
AC:
654
AN:
152290
Hom.:
5
Cov.:
31
AF XY:
0.00414
AC XY:
308
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00144
Gnomad4 AMR
AF:
0.00497
Gnomad4 ASJ
AF:
0.0173
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00122
Gnomad4 NFE
AF:
0.00622
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00703
Hom.:
8
Bravo
AF:
0.00475
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00774
EpiControl
AF:
0.00634

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.67
CADD
Benign
2.1
DANN
Benign
0.90
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs115985482; hg19: chr1-16046324; API