19-18010343-C-A

Position:

• chr19-18010343-C-A

Variant summary

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

The ENST00000222250.5(ARRDC2):​c.997C>A​(p.Pro333Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 3.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARRDC2	NM_015683.2	c.997C>A	p.Pro333Thr	missense_variant	6/8	ENST00000222250.5	NP_056498.1
ARRDC2	NM_001286826.2	c.997C>A	p.Pro333Thr	missense_variant	6/8		NP_001273755.1
ARRDC2	NM_001025604.3	c.982C>A	p.Pro328Thr	missense_variant	6/8		NP_001020775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARRDC2	ENST00000222250.5	c.997C>A	p.Pro333Thr	missense_variant	6/8	1	NM_015683.2	ENSP00000222250	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 11, 2022

The c.997C>A (p.P333T) alteration is located in exon 6 (coding exon 6) of the ARRDC2 gene. This alteration results from a C to A substitution at nucleotide position 997, causing the proline (P) at amino acid position 333 to be replaced by a threonine (T). 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	Benign	0.097
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.17
Sift	Benign	0.044	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.54		.;Gain of phosphorylation at P333 (P = 0.0149);
MVP		0.57
MPC		1.2
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.19
gMVP		0.73

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: rs2033386336; hg19: chr19-18121152;