rs367663991

Variant names:

• chr1-15716228-TTC-T
• rs367663991
• NM_015164.4:c.61-7_61-6delCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_015164.4(PLEKHM2):​c.61-7_61-6delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,421,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.281
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0041) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP6: Variant 1-15716228-TTC-T is Benign according to our data. Variant chr1-15716228-TTC-T is described in ClinVar as Benign. ClinVar VariationId is 478102.Status of the report is criteria_provided_single_submitter, 1 stars.

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.61-7_61-6delCT		splice_region intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.61-7_61-6delCT		splice_region intron	N/A	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.61-8_61-7delTC		splice_region intron	N/A	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.61-8_61-7delTC		splice_region intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.61-8_61-7delTC		splice_region intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150632 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00305 AC: 537 AN: 175796 AF XY: 0.00302

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00277

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.00256 AC: 3257 AN: 1270980 Hom.: 0 AF XY: 0.00250 AC XY: 1580 AN XY: 631406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00477 AC: 129 AN: 27030

American (AMR) AF: 0.00165 AC: 59 AN: 35650

Ashkenazi Jewish (ASJ) AF: 0.00286 AC: 65 AN: 22742

East Asian (EAS) AF: 0.000294 AC: 11 AN: 37404

South Asian (SAS) AF: 0.00146 AC: 109 AN: 74634

European-Finnish (FIN) AF: 0.00347 AC: 151 AN: 43548

Middle Eastern (MID) AF: 0.00178 AC: 9 AN: 5052

European-Non Finnish (NFE) AF: 0.00267 AC: 2598 AN: 971902

Other (OTH) AF: 0.00238 AC: 126 AN: 53018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150744 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73690

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000488 AC: 2 AN: 40958

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.000287 AC: 3 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67408

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs367663991; hg19: chr1-16042723; COSMIC: COSV65396743; COSMIC: COSV65396743;