chr22-29793666-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032204.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCC2	NM_032204.5	MANE Select	c.1699G>A	p.Glu567Lys	missense	Exon 16 of 20	NP_115580.2
	ASCC2	NM_001369920.1		c.1699G>A	p.Glu567Lys	missense	Exon 16 of 20	NP_001356849.1
	ASCC2	NM_001369921.1		c.1699G>A	p.Glu567Lys	missense	Exon 18 of 22	NP_001356850.1	Q9H1I8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCC2	ENST00000307790.8	TSL:1 MANE Select	c.1699G>A	p.Glu567Lys	missense	Exon 16 of 20	ENSP00000305502.3	Q9H1I8-1
	ASCC2	ENST00000865578.1		c.1822G>A	p.Glu608Lys	missense	Exon 18 of 22	ENSP00000535637.1
	ASCC2	ENST00000865580.1		c.1804G>A	p.Glu602Lys	missense	Exon 17 of 21	ENSP00000535639.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000171 AC: 3 AN: 175388 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000681

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32184

American (AMR) AF: 0.00 AC: 0 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 36746

South Asian (SAS) AF: 0.00 AC: 0 AN: 81334

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47810

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5720

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089098

Other (OTH) AF: 0.00 AC: 0 AN: 58706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0881482), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000844 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N
PhyloP100		3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.059
Sift	Benign	0.71	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.23		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
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs775769576; hg19: chr22-30189655;