chr19-45213106-C-T

Position:

chr19-45213106-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001382422.1(EXOC3L2):c.2372G>A(p.Arg791Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,536,724 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R791W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 31)

Exomes 𝑓: 0.017 ( 238 hom. )

Consequence

EXOC3L2
NM_001382422.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

Variant links:

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]

EXOC3L2 links:

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]

MARK4 links:

BLOC1S3 (HGNC:20914): (biogenesis of lysosomal organelles complex 1 subunit 3) This gene encodes a protein that is a component of the BLOC1 multi-subunit protein complex. This complex is necessary for the biogenesis of specialized organelles of the endosomal-lysosomal system, including platelet dense granules and melanosomes. Mutations in this gene cause Hermansky-Pudlak syndrome 8, a disease characterized by lysosomal storage defects, bleeding due to platelet storage pool deficiency, and oculocutaneous albinism. [provided by RefSeq, Jul 2008]

BLOC1S3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048166215).

BP6

Variant 19-45213106-C-T is Benign according to our data. Variant chr19-45213106-C-T is described in ClinVar as [Benign]. Clinvar id is 1662737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0116 (1759/152146) while in subpopulation SAS AF= 0.0234 (113/4822). AF 95% confidence interval is 0.0199. There are 19 homozygotes in gnomad4. There are 880 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EXOC3L2	NM_001382422.1 linkuse as main transcript	c.2372G>A	p.Arg791Gln	missense_variant	12/12	ENST00000413988.3
BLOC1S3	XR_007066811.1 linkuse as main transcript	n.1527-3570C>T		intron_variant, non_coding_transcript_variant
BLOC1S3	XR_007066813.1 linkuse as main transcript	n.1499-3570C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXOC3L2	ENST00000413988.3 linkuse as main transcript	c.2372G>A	p.Arg791Gln	missense_variant	12/12	5	NM_001382422.1	P1
MARK4	ENST00000587566.5 linkuse as main transcript	c.-276-45883C>T		intron_variant		5
BLOC1S3	ENST00000591569.1 linkuse as main transcript	n.283-3570C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1759

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0143

AC:

2357

AN:

165328

Hom.:

AF XY:

0.0153

AC XY:

1383

AN XY:

90372

show subpopulations

Gnomad AFR exome

AF:

0.00306

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00528

Gnomad EAS exome

AF:

0.000152

Gnomad SAS exome

AF:

0.0235

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0172

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0167

AC:

23161

AN:

1384578

Hom.:

238

Cov.:

AF XY:

0.0171

AC XY:

11691

AN XY:

682520

show subpopulations

Gnomad4 AFR exome

AF:

0.00228

Gnomad4 AMR exome

AF:

0.00386

Gnomad4 ASJ exome

AF:

0.00515

Gnomad4 EAS exome

AF:

0.000159

Gnomad4 SAS exome

AF:

0.0265

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0138

GnomAD4 genome

AF:

0.0116

AC:

1759

AN:

152146

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

880

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.00720

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0234

Gnomad4 FIN

AF:

0.0181

Gnomad4 NFE

AF:

0.0173

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.00980

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00301

AC:

ESP6500EA

AF:

0.0127

AC:

108

ExAC

AF:

0.0128

AC:

1540

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.024

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

0.46

.;P

Vest4

0.082

MPC

0.14

ClinPred

0.049

GERP RS

1.3

Varity_R

0.056

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over