11-2269920-G-C

Variant names:

• chr11-2269920-G-C
• rs1436779327
• NM_005170.3:c.413C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_005170.3(ASCL2):​c.413C>G​(p.Pro138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,131,514 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. P138L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1610409).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.413C>G	p.Pro138Arg	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.413C>G	p.Pro138Arg	missense	Exon 1 of 2	ENSP00000332293.4	Q99929

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000442 AC: 5 AN: 1131514 Hom.: 0 Cov.: 34 AF XY: 0.00000555 AC XY: 3 AN XY: 540076

African (AFR) AF: 0.00 AC: 0 AN: 23010

American (AMR) AF: 0.000118 AC: 1 AN: 8448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14914

East Asian (EAS) AF: 0.00 AC: 0 AN: 26610

South Asian (SAS) AF: 0.00 AC: 0 AN: 31740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3050

European-Non Finnish (NFE) AF: 0.00000424 AC: 4 AN: 943460

Other (OTH) AF: 0.00 AC: 0 AN: 45334

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.4
DANN	Benign	0.29
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.23
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.10
Sift	Benign	0.53	T
Sift4G	Benign	0.17	T
Polyphen		0.13	B
Vest4		0.046
MutPred		0.30		Gain of MoRF binding (P = 2e-04)
MVP		0.74
MPC		1.3
ClinPred		0.036	T
GERP RS		1.2
Varity_R		0.030
gMVP		0.26
Mutation Taster		=88/12	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: rs1436779327; hg19: chr11-2291150;