22-29793608-C-A

Variant names:

• chr22-29793608-C-A
• NM_032204.5:c.1757G>T

Variant summary

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

The NM_032204.5(ASCC2):​c.1757G>T​(p.Arg586Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ASCC2 NM_032204.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87

Genes affected

ASCC2 (HGNC:24103): (activating signal cointegrator 1 complex subunit 2) Predicted to enable ubiquitin binding activity. Involved in regulation of transcription, DNA-templated; rescue of stalled ribosome; and ribosome-associated ubiquitin-dependent protein catabolic process. Located in nucleus. Part of activating signal cointegrator 1 complex. [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 rank	MANE	Protein	UniProt
ASCC2	NM_032204.5	c.1757G>T	p.Arg586Leu	missense_variant	Exon 16 of 20	ENST00000307790.8	NP_115580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCC2	ENST00000307790.8	c.1757G>T	p.Arg586Leu	missense_variant	Exon 16 of 20	1	NM_032204.5	ENSP00000305502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456330 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724336

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: 0.00000360

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 specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1757G>T (p.R586L) alteration is located in exon 16 (coding exon 15) of the ASCC2 gene. This alteration results from a G to T substitution at nucleotide position 1757, causing the arginine (R) at amino acid position 586 to be replaced by a leucine (L). 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	0.30
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N;D
REVEL	Benign	0.23
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.20	T;T;T;D
Polyphen		1.0	D;.;D;.
Vest4		0.86
MutPred		0.46		Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);.;
MVP		0.46
MPC		0.58
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.48

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: chr22-30189597;