Variant 12-102958393-CGCAGCAGCAGCA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_004316.4(ASCL1):c.175_186del(p.Gln59_Gln62del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000855 in 1,507,074 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 0)

Exomes 𝑓: 0.00079 ( 2 hom. )

Consequence

ASCL1
NM_004316.4 inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.809

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 -6 ACMG points.

BP6

Variant 12-102958393-CGCAGCAGCAGCA-C is Benign according to our data. Variant chr12-102958393-CGCAGCAGCAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 259284.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-102958393-CGCAGCAGCAGCA-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASCL1	NM_004316.4 linkuse as main transcript	c.175_186del	p.Gln59_Gln62del	inframe_deletion	1/2	ENST00000266744.4
PAH	NM_001354304.2 linkuse as main transcript	c.-306_-295del		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.175_186del	p.Gln59_Gln62del	inframe_deletion	1/2	1	NM_004316.4	P1
PAH	ENST00000547319.1 linkuse as main transcript	n.6_17del		non_coding_transcript_exon_variant	1/3	4
PAH	ENST00000551337.5 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

222

AN:

150116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00119

Gnomad ASJ

AF:

0.00694

Gnomad EAS

AF:

0.000394

Gnomad SAS

AF:

0.00210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000683

Gnomad OTH

AF:

0.00146

GnomAD4 exome

AF:

0.000787

AC:

1068

AN:

1356868

Hom.:

AF XY:

0.000844

AC XY:

565

AN XY:

669194

show subpopulations

Gnomad4 AFR exome

AF:

0.00253

Gnomad4 AMR exome

AF:

0.000802

Gnomad4 ASJ exome

AF:

0.00583

Gnomad4 EAS exome

AF:

0.000839

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000541

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.00147

AC:

221

AN:

150206

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

119

AN XY:

73322

show subpopulations

Gnomad4 AFR

AF:

0.00290

Gnomad4 AMR

AF:

0.00119

Gnomad4 ASJ

AF:

0.00694

Gnomad4 EAS

AF:

0.000396

Gnomad4 SAS

AF:

0.00189

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000683

Gnomad4 OTH

AF:

0.00145

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

ASCL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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