16-57248626-C-A

Position:

• chr16-57248626-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000219204.8(ARL2BP):​c.190C>A​(p.Pro64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ARL2BP ENST00000219204.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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]

LOC124903697 (HGNC:):

PLLP (HGNC:18553): (plasmolipin) Predicted to be a structural constituent of myelin sheath. Predicted to be involved in myelination. Predicted to be located in compact myelin and membrane raft. Predicted to be integral component of membrane. Biomarker of schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10351694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARL2BP	NM_012106.4	c.190C>A	p.Pro64Thr	missense_variant	3/6	ENST00000219204.8	NP_036238.1
LOC124903697	XR_007065082.1	n.1435G>T		non_coding_transcript_exon_variant	2/2
ARL2BP	XM_047433883.1	c.94C>A	p.Pro32Thr	missense_variant	3/6		XP_047289839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARL2BP	ENST00000219204.8	c.190C>A	p.Pro64Thr	missense_variant	3/6	1	NM_012106.4	ENSP00000219204	P1
ARL2BP	ENST00000563234.1	c.184C>A	p.Pro62Thr	missense_variant	3/6	2		ENSP00000454237
ARL2BP	ENST00000562023.5	c.101-1154C>A		intron_variant		3		ENSP00000457465
PLLP	ENST00000564376.1	n.321G>T		splice_region_variant, non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431006 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 712000

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: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ARL2BP-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 64 of the ARL2BP protein (p.Pro64Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.073
Sift	Benign	0.32	T
Sift4G	Benign	0.46	T
Polyphen		0.0060	B
Vest4		0.27
MutPred		0.29		Loss of loop (P = 0.1242);
MVP		0.24
MPC		0.56
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.54

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: rs2075398122; hg19: chr16-57282538;