22-29793666-C-T

Variant names:

• chr22-29793666-C-T
• rs775769576
• NM_032204.5:c.1699G>A

Variant summary

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

The NM_032204.5(ASCC2):​c.1699G>A​(p.Glu567Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,414,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ASCC2 NM_032204.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.34

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08230513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCC2	NM_032204.5	c.1699G>A	p.Glu567Lys	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.1699G>A	p.Glu567Lys	missense_variant	Exon 16 of 20	1	NM_032204.5	ENSP00000305502.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1414260 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700064

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: 0.0000209

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000844 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1699G>A (p.E567K) alteration is located in exon 16 (coding exon 15) of the ASCC2 gene. This alteration results from a G to A substitution at nucleotide position 1699, causing the glutamic acid (E) at amino acid position 567 to be replaced by a lysine (K). 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	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.0045	T;.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.66	N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.32
MutPred		0.23		Gain of methylation at E567 (P = 0.0112);.;Gain of methylation at E567 (P = 0.0112);.;
MVP		0.30
MPC		0.37
ClinPred		0.11	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.22

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: rs775769576; hg19: chr22-30189655;