Variant chr12-102958393-C-CGCAGCAGCAGCAGCAGCAGCA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004316.4(ASCL1):c.166_186dup(p.Gln56_Gln62dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ASCL1
NM_004316.4 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.219

Variant links:

Genes affected

ASCL1 (HGNC:738): (achaete-scute family bHLH transcription factor 1) This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]

ASCL1 links:

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 117 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4 linkuse as main transcript	c.166_186dup	p.Gln56_Gln62dup	inframe_insertion	1/2	ENST00000266744.4
PAH	NM_001354304.2 linkuse as main transcript	c.-295_-294insTGCTGCTGCTGCTGCTGCTGC		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ASCL1	ENST00000266744.4 linkuse as main transcript	c.166_186dup	p.Gln56_Gln62dup	inframe_insertion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1 linkuse as main transcript	n.17_18insTGCTGCTGCTGCTGCTGCTGC		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000779

AC:

117

AN:

150120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000462

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

162

AN:

1356934

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

669230

show subpopulations

Gnomad4 AFR exome

AF:

0.00225

Gnomad4 AMR exome

AF:

0.000297

Gnomad4 ASJ exome

AF:

0.0000833

Gnomad4 EAS exome

AF:

0.000779

Gnomad4 SAS exome

AF:

0.000171

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000302

Gnomad4 OTH exome

AF:

0.000213

GnomAD4 genome

AF:

0.000779

AC:

117

AN:

150210

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

AN XY:

73326

show subpopulations

Gnomad4 AFR

AF:

0.00259

Gnomad4 AMR

AF:

0.000462

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000198

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ASCL1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The ASCL1 c.166_186dup21 variant is predicted to result in an in-frame duplication (p.Gln56_Gln62dup). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over