11-2270196-C-T

Variant names:

• chr11-2270196-C-T
• rs771052351
• NM_005170.3:c.137G>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.137G>A​(p.Gly46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,078 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G46A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• 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=0.38723963).

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.137G>A	p.Gly46Glu	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.137G>A	p.Gly46Glu	missense	Exon 1 of 2	ENSP00000332293.4	Q99929

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000107 AC: 1 AN: 93660 AF XY: 0.0000184

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: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1337078 Hom.: 0 Cov.: 34 AF XY: 0.00000303 AC XY: 2 AN XY: 660246

African (AFR) AF: 0.00 AC: 0 AN: 27524

American (AMR) AF: 0.00 AC: 0 AN: 28022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23328

East Asian (EAS) AF: 0.00 AC: 0 AN: 29852

South Asian (SAS) AF: 0.00 AC: 0 AN: 74286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1058966

Other (OTH) AF: 0.00 AC: 0 AN: 55372

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000102 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.20	T
Polyphen		0.84	P
Vest4		0.25
MutPred		0.28		Loss of MoRF binding (P = 0.0576)
MVP		0.87
MPC		2.2
ClinPred		0.15	T
GERP RS		2.7
PromoterAI		-0.051	Neutral
Varity_R		0.16
gMVP		0.22
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: rs771052351; hg19: chr11-2291426;