chr11-2270105-G-T

Variant names:

• chr11-2270105-G-T
• rs374798855
• NM_005170.3:c.228C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005170.3(ASCL2):​c.228C>A​(p.His76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,362 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ASCL2 NM_005170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.869
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.228C>A	p.His76Gln	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.228C>A	p.His76Gln	missense	Exon 1 of 2	ENSP00000332293.4	Q99929

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360362 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 672498

African (AFR) AF: 0.00 AC: 0 AN: 28208

American (AMR) AF: 0.00 AC: 0 AN: 31498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23928

East Asian (EAS) AF: 0.00 AC: 0 AN: 31100

South Asian (SAS) AF: 0.00 AC: 0 AN: 76282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4828

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1067954

Other (OTH) AF: 0.00 AC: 0 AN: 56392

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.87
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.81
Sift	Benign	0.050	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.57		Gain of disorder (P = 0.0856)
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		0.42	Neutral
Varity_R		0.65
gMVP		0.61
Mutation Taster		=45/55	disease causing

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: rs374798855; hg19: chr11-2291335;