Variant 16-57248644-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_012106.4(ARL2BP):c.207+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ARL2BP
NM_012106.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.56

Variant links:

Genes affected

ARL2BP (HGNC:17146): (ADP ribosylation factor like GTPase 2 binding protein) ADP-ribosylation factor (ARF)-like proteins (ARLs) comprise a functionally distinct group of the ARF family of RAS-related GTPases. The protein encoded by this gene binds to ARL2.GTP with high affinity but does not interact with ARL2.GDP, activated ARF, or RHO proteins. The lack of detectable membrane association of this protein or ARL2 upon activation of ARL2 is suggestive of actions distinct from those of the ARFs. This protein is considered to be the first ARL2-specific effector identified, due to its interaction with ARL2.GTP but lack of ARL2 GTPase-activating protein activity. [provided by RefSeq, Jul 2008]

ARL2BP links:

LOC124903697 (HGNC:):

LOC124903697 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.2, offset of 31, new splice context is: gagGTcaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
ARL2BP	NM_012106.4 linkuse as main transcript	c.207+1G>C	splice_donor_variant, intron_variant		ENST00000219204.8	NP_036238.1	Q9Y2Y0-1A0A024R6U9
ARL2BP	XM_047433883.1 linkuse as main transcript	c.111+1G>C	splice_donor_variant, intron_variant			XP_047289839.1
LOC124903697	XR_007065082.1 linkuse as main transcript	n.1417C>G	non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ARL2BP	ENST00000219204.8 linkuse as main transcript	c.207+1G>C	splice_donor_variant, intron_variant	1	NM_012106.4	ENSP00000219204.3	Q9Y2Y0-1
ARL2BP	ENST00000563234.1 linkuse as main transcript	c.198+1G>C	splice_donor_variant, intron_variant	2		ENSP00000454237.1	H3BM52
ARL2BP	ENST00000562023.5 linkuse as main transcript	c.101-1136G>C	intron_variant	3		ENSP00000457465.1	H3BU49
PLLP	ENST00000564376.1 linkuse as main transcript	n.321-18C>G	intron_variant	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000464

AC:

AN:

215538

Hom.:

AF XY:

0.00000854

AC XY:

AN XY:

117078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000434

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370214

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682746

show subpopulations

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:

0.0000134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over