chr11-2270256-G-A

Variant names:

• chr11-2270256-G-A
• rs754330551
• NM_005170.3:c.77C>T

Variant summary

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

The NM_005170.3(ASCL2):​c.77C>T​(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. P26R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47
• 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=0.31474352).

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.77C>T	p.Pro26Leu	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.77C>T	p.Pro26Leu	missense	Exon 1 of 2	ENSP00000332293.4	Q99929

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1251046 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 612006

African (AFR) AF: 0.00 AC: 0 AN: 24798

American (AMR) AF: 0.00 AC: 0 AN: 15410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19272

East Asian (EAS) AF: 0.00 AC: 0 AN: 27496

South Asian (SAS) AF: 0.00 AC: 0 AN: 60500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016834

Other (OTH) AF: 0.00 AC: 0 AN: 51600

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.028	D
Sift4G	Benign	0.14	T
Polyphen		0.74	P
Vest4		0.052
MutPred		0.18		Loss of glycosylation at P26 (P = 0.0095)
MVP		0.89
MPC		1.1
ClinPred		0.61	D
GERP RS		2.7
PromoterAI		0.056	Neutral
Varity_R		0.089
gMVP		0.45
Mutation Taster		=91/9	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: rs754330551; hg19: chr11-2291486;