19-18009676-C-G

Position:

• chr19-18009676-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000222250.5(ARRDC2):​c.574C>G​(p.Arg192Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARRDC2 ENST00000222250.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

ARRDC2 (HGNC:25225): (arrestin domain containing 2) Predicted to be involved in protein transport. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARRDC2	NM_015683.2	c.574C>G	p.Arg192Gly	missense_variant	4/8	ENST00000222250.5	NP_056498.1
ARRDC2	NM_001286826.2	c.574C>G	p.Arg192Gly	missense_variant	4/8		NP_001273755.1
ARRDC2	NM_001025604.3	c.559C>G	p.Arg187Gly	missense_variant	4/8		NP_001020775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARRDC2	ENST00000222250.5	c.574C>G	p.Arg192Gly	missense_variant	4/8	1	NM_015683.2	ENSP00000222250	P1
	ENST00000624199.1	n.206G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.574C>G (p.R192G) alteration is located in exon 4 (coding exon 4) of the ARRDC2 gene. This alteration results from a C to G substitution at nucleotide position 574, causing the arginine (R) at amino acid position 192 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.4	.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.3	D;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.96
MutPred		0.50		.;.;Loss of MoRF binding (P = 0.0185);
MVP		0.50
MPC		1.5
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18120485;