11-2270302-G-T

Variant names:

• chr11-2270302-G-T
• rs1453827508
• NM_005170.3:c.31C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005170.3(ASCL2):​c.31C>A​(p.Pro11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000845 in 1,182,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. P11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.341
• Publications: 0 publications found

Genes affected

ASCL2 (HGNC:739): (achaete-scute family bHLH transcription factor 2) This gene is a member of the basic helix-loop-helix (BHLH) family of transcription factors. It activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. Involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27767217).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005170.3. 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
	ASCL2	NM_005170.3	MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 2	NP_005161.1	Q99929

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL2	ENST00000331289.5	TSL:1 MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 2	ENSP00000332293.4	Q99929

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.45e-7 AC: 1 AN: 1182818 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 570806

African (AFR) AF: 0.00 AC: 0 AN: 23396

American (AMR) AF: 0.00 AC: 0 AN: 8818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16082

East Asian (EAS) AF: 0.00 AC: 0 AN: 27004

South Asian (SAS) AF: 0.00 AC: 0 AN: 44878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 982368

Other (OTH) AF: 0.0000206 AC: 1 AN: 48558

GnomAD4 genome Cov.: 34

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	0.070
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.34
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Polyphen		0.92	P
Vest4		0.070
MutPred		0.26		Gain of phosphorylation at P11 (P = 0.0033)
MVP		0.80
MPC		1.2
ClinPred		0.27	T
GERP RS		2.6
PromoterAI		0.037	Neutral
Varity_R		0.12
gMVP		0.53
Mutation Taster		=82/18	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: rs1453827508; hg19: chr11-2291532;