chr19-45227667-T-TG

Variant names:

• chr19-45227667-T-TG
• rs886039793
• NM_001382422.1:c.1577dupC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001382422.1(EXOC3L2):​c.1577dupC​(p.Leu527ThrfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000686 in 1,458,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EXOC3L2 NM_001382422.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.04

Genes affected

EXOC3L2 (HGNC:30162): (exocyst complex component 3 like 2) The protein encoded by this gene is upregulated by vascular endothelial growth factor A and interacts with exocyst complex component 4. The encoded protein may be part of an exocyst complex that plays a role in cell membrane dynamics. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, May 2017]

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45227667-T-TG is Pathogenic according to our data. Variant chr19-45227667-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 266076.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC3L2	NM_001382422.1	c.1577dupC	p.Leu527ThrfsTer25	frameshift_variant	Exon 7 of 12	ENST00000413988.3	NP_001369351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC3L2	ENST00000413988.3	c.1577dupC	p.Leu527ThrfsTer25	frameshift_variant	Exon 7 of 12	5	NM_001382422.1	ENSP00000400713.2
MARK4	ENST00000587566.5	c.-276-31316dupG		intron_variant	Intron 1 of 6	5		ENSP00000465414.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Meckel-Gruber syndrome Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

LOF, autozygosity mapping -

Brain malformation renal syndrome Pathogenic:1

Sep 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs886039793; hg19: chr19-45730925;