chr1-15718592-C-T

Variant names:

• chr1-15718592-C-T
• rs201860640
• NM_015164.4:c.432C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_015164.4(PLEKHM2):​c.432C>T​(p.Ser144Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,394,892 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.69
• Publications: 0 publications found

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]

PLEKHM2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-15718592-C-T is Benign according to our data. Variant chr1-15718592-C-T is described in ClinVar as Benign. ClinVar VariationId is 478099.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. 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
	PLEKHM2	NM_015164.4	MANE Select	c.432C>T	p.Ser144Ser	synonymous	Exon 5 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.432C>T	p.Ser144Ser	synonymous	Exon 5 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.432C>T	p.Ser144Ser	synonymous	Exon 5 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.432C>T	p.Ser144Ser	synonymous	Exon 5 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.432C>T	p.Ser144Ser	synonymous	Exon 5 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 206 AN: 141678 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000243

Gnomad SAS AF: 0.000997

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00233

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00142 AC: 277 AN: 195340 AF XY: 0.00149

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.000828

Gnomad ASJ exome AF: 0.000550

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00262 AC: 3277 AN: 1253084 Hom.: 9 Cov.: 31 AF XY: 0.00264 AC XY: 1632 AN XY: 618346

African (AFR) AF: 0.000291 AC: 8 AN: 27532

American (AMR) AF: 0.000836 AC: 29 AN: 34696

Ashkenazi Jewish (ASJ) AF: 0.000528 AC: 10 AN: 18946

East Asian (EAS) AF: 0.00 AC: 0 AN: 20962

South Asian (SAS) AF: 0.00132 AC: 105 AN: 79694

European-Finnish (FIN) AF: 0.000108 AC: 4 AN: 37198

Middle Eastern (MID) AF: 0.00126 AC: 6 AN: 4772

European-Non Finnish (NFE) AF: 0.00307 AC: 3016 AN: 981792

Other (OTH) AF: 0.00208 AC: 99 AN: 47492

GnomAD4 genome AF: 0.00145 AC: 205 AN: 141808 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 88 AN XY: 68626

African (AFR) AF: 0.000718 AC: 28 AN: 38996

American (AMR) AF: 0.00130 AC: 18 AN: 13864

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3354

East Asian (EAS) AF: 0.000244 AC: 1 AN: 4106

South Asian (SAS) AF: 0.000994 AC: 4 AN: 4024

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 8986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00233 AC: 152 AN: 65330

Other (OTH) AF: 0.00 AC: 0 AN: 1994

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.00139

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-2.7
Mutation Taster		=98/2	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: rs201860640; hg19: chr1-16045087;