11-2269962-G-C

Position:

• chr11-2269962-G-C

Variant summary

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

The NM_005170.3(ASCL2):​c.371C>G​(p.Ala124Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,148,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.903

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

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=0.21663734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASCL2	NM_005170.3	c.371C>G	p.Ala124Gly	missense_variant	1/2	ENST00000331289.5	NP_005161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASCL2	ENST00000331289.5	c.371C>G	p.Ala124Gly	missense_variant	1/2	1	NM_005170.3	ENSP00000332293.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000261 AC: 3 AN: 1148544 Hom.: 0 Cov.: 34 AF XY: 0.00000363 AC XY: 2 AN XY: 550736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000380

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000209

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.371C>G (p.A124G) alteration is located in exon 1 (coding exon 1) of the ASCL2 gene. This alteration results from a C to G substitution at nucleotide position 371, causing the alanine (A) at amino acid position 124 to be replaced by a glycine (G). 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	0.071
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.86
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.26
Sift	Benign	0.43	T
Sift4G	Benign	0.53	T
Polyphen		0.12	B
Vest4		0.086
MutPred		0.13		Loss of MoRF binding (P = 0.1219);
MVP		0.89
MPC		1.4
ClinPred		0.11	T
GERP RS		4.0
Varity_R		0.050
gMVP		0.30

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: rs1287172752; hg19: chr11-2291192;